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Background: Colorectal cancer (CRC) is one of the most common malignancies and the patient survival rate remains unacceptably low. The anti-programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) antibody-based immune checkpoint inhibitors have been added to CRC treatment regimens, however, only a fraction of patients benefits. As an important co-stimulatory molecule, 4-1BB/CD137 is mainly expressed on the surface of immune cells including T and natural killer (NK) cells. Several agonistic molecules targeting 4-1BB have been clinically unsuccessful due to systemic toxicity or weak antitumor effects. We generated a humanized anti-4-1BB IgG4 antibody, HuB6, directed against a unique epitope and hypothesized that it would promote antitumor immunity with high safety.Methods: The antigen binding specificity, affinity and activity of HuB6 were determined by enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR), biolayer interferometry (BLI) and flow cytometry. The antitumor effects were evaluated in humanized mice bearing syngeneic tumors, and possible toxicity was evaluated in humanized mice and cynomolgus monkeys.Results: HuB6 showed high specificity and affinity for a binding epitope distinct from those of other known 4-1BB agonists, including utomilumab and urelumab, and induced CD8 + T, CD4 + T and NK cell stimulation dependent on Fcγ receptor (FcγR) crosslinking. HuB6 inhibited CRC tumor growth in a dose-dependent manner, and the antitumor effect was similar with urelumab and utomilumab in humanized mouse models of syngeneic CRC. Furthermore, HuB6 combined with an anti-PD-L1 antibody significantly inhibited CRC growth in vivo. Additionally, HuB6 induced antitumor immune memory in tumor model mice rechallenged with 4 × 106 tumor cells. Toxicology data for humanized 4-1BB mice and cynomolgus monkeys showed that HuB6 could be tolerated up to a 180 mg/kg dose without systemic toxicity.Conclusions: This study demonstrated that HuB6 should be a suitable candidate for further clinical development and a potential agent for CRC immunotherapy. [ABSTRACT FROM AUTHOR]

Gas plasma is a partially ionized gas operated at body temperature, expelling various reactive oxygen species (ROS) in chorus. While the technology's anticancer potential is generally appreciated, exciting progress in experimental gas plasma therapy for breast cancer has been made recently, particularly in empowering anticancer immunity. [ABSTRACT FROM AUTHOR]

Background: Cholangiocarcinoma (CCA) is a class of malignant tumors originating from bile duct epithelial cells. Due to difficult early diagnosis and limited treatment, the prognosis of CCA is extremely poor. BMI1 is dysregulated in many human malignancies. However, the prognostic significance and oncogenic role of BMI1 in cholangiocarcinoma (CCA) are not well elucidated. Methods: In the present study, we investigated its clinical importance and the potential mechanisms in the progression of CCA. We detected BMI1 expression in a large CCA cohort. We demonstrated that BMI1 was substantially upregulated in CCA tissues and was identified as an independent prognostic biomarker of CCA. Moreover, overexpression of BMI1 promoted CCA proliferation, migration, and invasion. And BMI1 knockdown could inhibit proliferation and metastases of CCA in vitro and in vitro/vivo validation. Interestingly, we found that CCA-derived exosomes contain BMI1 proteins, which can transfer BMI1 between CCA cells. The unique BMI1-containing exosomes promote CCA proliferation and metastasis through autocrine/paracrine mechanisms. In addition, we demonstrated that BMI1 inhibits CD8+T cell-recruiting chemokines by promoting repressive H2A ubiquitination in CCA cells. Conclusions: BMI1 is an unfavorable prognostic biomarker of CCA. Our data depict a novel function of BMI1 in CCA tumorigenesis and metastasis mediated by exosomes. Besides, BMI1 inhibition may augment immune checkpoint blockade to inhibit tumor progression by activating cell-intrinsic immunity of CCA. [ABSTRACT FROM AUTHOR]

Transforming growth factor-beta (TGF-β) pathway mediates suppression of antitumor immunity and is associated with poor prognosis in triple-negative breast cancer (TNBC). In this study, we generated a humanized animal model by transplanting human peripheral blood mononuclear cells into immunodeficient mice followed by inoculation of MDA-MB-231 cells and subsequently analyzed the role of TGF-β2 in the interaction between human T cells and human tumor cells. Following reconstitution of the human immune system, inhibition of TGF-β signaling by TGF-β2 antisense oligodeoxynucleotide (TASO) resulted in accelerated tumor growth inhibition. TGF-β2 inhibition also resulted in downregulation of peripheral Foxp3 + regulatory T cells (Treg), whereas no effect was seen in the expression of CD8 + cytotoxic T cells. Analysis of the TASO-treated mice serum revealed elevated levels of human IFN-γ and reduced levels of human IL-10 and TGF-β2. Moreover, TGF-β2 inhibition resulted in increased CD8 + T cell infiltration, whereas the reduced infiltration of Tregs into the tumor partly resulted from decreased expression of CCL22. Decreased intratumoral Tregs facilitated the activation of cytotoxic T cells, associated with increased granzyme B expression. These results indicate that TASO potentiated T cell-mediated antitumor immunity, and it is proposed that TGF-β2 may be a promising target in the immunotherapeutic strategy of TNBC. [ABSTRACT FROM AUTHOR]

Marine seaweeds are important sources of drugs with several pharmacological characteristics. The present study aims to evaluate the antitumor and antitumor immunological potentials of the extracts from the brown alga Padinapavonica and the red alga Janiarubens, inhibiting the Egyptian marine coasts. Hep-G2 cell lines were used for assessment of the antitumor efficacy of Padinapavonica and Janiarubens extracts in vitro, while Ehrlich ascites carcinoma (EAC) cells were applied to gain more antitumor immunity and antitumor insights of P.pavonica and J.rubens extracts in vivo. In vitro antitumor potentials of P.pavonica and J.rubens extracts were analyzed against human liver cancer Hep-G2 cells by MTT and trypan blue exclusion assays. In vivo antitumor immunological potentials of P.pavonica and J.rubens extracts at low, high, and prophylactic doses were analyzed by blood counting and flow cytometry in mice challenged with Ehrlich ascites carcinoma (EAC) cells. In vitro results revealed that P.pavonica and J.rubens extracts caused significant decreases in the number and viability of Hep-G2 cells in a dose-dependent manner as compared to untreated Hep-G2 cells or Cisplatin®-treated Hep-G2 cells. In vivo findings showed that P.pavonica and J.rubens extracts at low, high, and prophylactic doses significantly reduced the number and viability of EAC tumor cells accompanied by increases in EAC apoptosis compared to naïve EAC mouse. Additionally, P.pavonica and J.rubens extracts at low and prophylactic doses remarkably increased both the total WBC count and the relative numbers of lymphocytes and decreased the relative numbers of neutrophils and monocytes. Flow cytometric analysis showed that P.pavonica and J.rubens extracts at the treatment and the prophylactic doses resulted in a significant increase in the phenotypic expressions of CD4+ T, CD8+ T, and CD335 cells compared to naïve EAC mouse. Overall, both extracts P.pavonica and J.rubens possess potential antitumor and antitumor immunological effects with less toxicity, opening new approaches for further studies of the chemical and biological mechanisms behind these effects. [ABSTRACT FROM AUTHOR]

Chromosome instability (CIN) and its major consequence, aneuploidy, are hallmarks of human cancers. In addition to imposing fitness costs on tumor cells through several cell-intrinsic mechanisms, CIN/aneuploidy also provokes an antitumor immune response. However, as the major contributor to genomic instability, intratumor heterogeneity generated by CIN/aneuploidy helps tumor cells to evolve methods to overcome the antitumor role of the immune system or even convert the immune system to be tumor-promoting. Although the interplay between CIN/aneuploidy and the immune system is complex and context-dependent, understanding this interplay is essential for the success of immunotherapy in tumors exhibiting CIN/aneuploidy, regardless of whether the efficacy of immunotherapy is increased by combination with strategies to promote CIN/aneuploidy or by designing immunotherapies to target CIN/aneuploidy directly. [ABSTRACT FROM AUTHOR]

Simple Summary: Ion channels are proteins that control the movement of ions across the membranes of cells, thus regulating their physiological functions. In T lymphocytes, ion channels control the Ca2+ influx that, in turn, promotes proliferation and effector functions. In the context of cancer, T cells have the role of fighting tumor cells. However, the tumor microenvironment negatively regulates T cell antitumor capabilities. Therefore, it is of utmost importance to understand the relationship between the tumor microenvironment and the ion channel apparatus of T cells to overcome the tumors' immunosuppressive capabilities. Competent antitumor immune cells are fundamental for tumor surveillance and combating active cancers. Once established, tumors generate a tumor microenvironment (TME) consisting of complex cellular and metabolic elements that serve to suppress the function of antitumor immune cells. T lymphocytes are key cellular elements of the TME. In this review, we explore the role of ion channels, particularly K+ channels, in mediating the suppressive effects of the TME on T cells. First, we will review the complex network of ion channels that mediate Ca2+ influx and control effector functions in T cells. Then, we will discuss how multiple features of the TME influence the antitumor capabilities of T cells via ion channels. We will focus on hypoxia, adenosine, and ionic imbalances in the TME, as well as overexpression of programmed cell death ligand 1 by cancer cells that either suppress K+ channels in T cells and/or benefit from regulating these channels' activity, ultimately shaping the immune response. Finally, we will review some of the cancer treatment implications related to ion channels. A better understanding of the effects of the TME on ion channels in T lymphocytes could promote the development of more effective immunotherapies, especially for resistant solid malignancies. [ABSTRACT FROM AUTHOR]

Glycoproteins produced by tumor cells are involved in cancer progression, metastasis, and the immune response, and serve as possible therapeutic targets. Considering the dismal outcomes of pancreatic ductal adenocarcinoma (PDAC) due to its unique tumor microenvironment, which is characterized by low antitumor T‐cell infiltration, we hypothesized that tumor‐derived glycoproteins may serve as regulating the tumor microenvironment. We used glycoproteomics with tandem mass tag labeling to investigate the culture media of three human PDAC cell lines, and attempted to identify the key secreted proteins from PDAC cells. Among the identified glycoproteins, prosaposin (PSAP) was investigated for its functional contribution to PDAC progression. PSAP is highly expressed in various PDAC cell lines; however, knockdown of intrinsic PSAP expression did not affect the proliferation and migration capacities. Based on the immunohistochemistry of resected human PDAC tissues, high PSAP expression was associated with poor prognosis in patients with PDAC. Notably, tumors with high PSAP expression showed significantly lower CD8+ T‐cell infiltration than those with low PSAP expression. Furthermore, PSAP stimulation decreased the proportion of CD8+ T cells in peripheral blood monocytes. Finally, in an orthotopic transplantation model, the number of CD8+ T cells in the PSAP shRNA groups was significantly increased, resulting in a decreased tumor volume compared with that in the control shRNA group. PSAP suppresses CD8+ T‐cell infiltration, leading to the promotion of PDAC progression. However, further studies are warranted to determine whether this study contributes to the development of a novel immunomodulating therapy for PDAC. [ABSTRACT FROM AUTHOR]

Cancer constitutes a significant threat to patients' lives worldwide. Immunotherapy, particularly immune checkpoint inhibitors (ICIs) that boost antitumor immunity by targeting immune checkpoint components, has emerged as a promising strategy for its treatment in recent years. However, the objective response rates of the ICIs are unsatisfactory. As the primary route, systemic administration of ICIs is often accompanied by immune-related adverse events. Local delivery of ICIs serves as a potential therapeutic strategy that can improve the efficacy while simultaneously reducing side effects through precise drug release at the tumor site. Initial validation of direct local application of ICIs for tumors in clinical trials has indicated reduced side effects and improved efficacy, while low bioavailability remains a challenge. Furthermore, research on various carriers, including nanoparticles, microneedles, hydrogels, combined platforms, and implantable devices for local release of ICIs has exhibited applying potential in treating murine tumors, among which combined platforms such as combined hydrogel system hold the highest promise due to their encompassment of the advantages of multiple carriers. These carriers, by incorporating ICIs and other therapeutics, could manage cancers more potently, which needs to be confirmed in clinical trials after the refinement of their biocompatibility. This review summarizes the latest research advancements regarding local administration of ICIs, with a particular focus on the carriers for local delivery as well as the combination therapies, thus providing novel insights and research guidance for scholars to enhance the efficacy of locally delivered ICIs on managing multiple cancers in the future.

Tumor Treating Fields (TTFields) therapy is a locoregional, anticancer treatment consisting of a noninvasive, portable device that delivers alternating electric fields to tumors through arrays placed on the skin. Based on efficacy and safety data from global pivotal (randomized phase III) clinical studies, TTFields therapy (Optune Gio) is US Food and Drug Administration-approved for newly diagnosed (nd) and recurrent glioblastoma (GBM) and Conformité Européenne-marked for grade 4 glioma. Here we review data on the multimodal TTFields mechanism of action that includes disruption of cancer cell mitosis, inhibition of DNA replication and damage response, interference with cell motility, and enhancement of systemic antitumor immunity (adaptive immunity). We describe new data showing that TTFields therapy has efficacy in a broad range of patients, with a tolerable safety profile extending to high-risk subpopulations. New analyses of clinical study data also confirmed that overall and progression-free survival positively correlated with increased usage of the device and dose of TTFields at the tumor site. Additionally, pilot/early phase clinical studies evaluating TTFields therapy in ndGBM concomitant with immunotherapy as well as radiotherapy have shown promise, and new pivotal studies will explore TTFields therapy in these settings. Finally, we review recent and ongoing studies in patients in pediatric care, other central nervous system tumors and brain metastases, as well as other advanced-stage solid tumors (ie, lung, ovarian, pancreatic, gastric, and hepatic cancers), that highlight the broad potential of TTFields therapy as an adjuvant treatment in oncology., (© The Author(s) 2024. Published by Oxford University Press.)

In this article, which is part of the Currents in One Health series, principles of immunotherapeutics are discussed and their clinical exploration in dogs reviewed with emphasis on their translatability for improving treatment of commonly diagnosed cancers. With increasing longevity and sustained quality of life in pet dogs through dietary, environmental awareness, and preventative medical practices, the geriatric pet population has continued to steadily grow and, consequently, so have age-related pathologies. Not surprisingly, cancer is the most common cause of mortality in elderly dogs, accounting for 1 in 4 deaths in dogs > 10 years of age. Importantly, some cancer types that arise spontaneously in pet dogs are similar to cancers afflicting people. The shared clinical and biological behaviors of certain cancers observed in pet dogs and people underscore the opportunity to leverage comparative oncology studies, which can accelerate the validation and clinical implementation of innovative therapies that can benefit pet dogs and ultimately guide these strategies toward clinical practice in people too. In the era of immunotherapy, the inclusion of pet dogs that develop cancers under an intact immune system affords a unique and high-value opportunity to study the evolving nature of cancers shaped by immunosurveillance pressures. Complementing these discovery efforts and through a comparative oncology approach, the exploration and clinical validation of novel immunotherapeutic strategies in pet dogs can be foundational for defining the safety and immune-activating potential of new anticancer immune approaches that hold promise to transform cancer treatment in both pets and people alike.

The clinical use of immunostimulatory polyinosinic:polycytidylic acid (pIC) for cancer therapy has been notably limited by its low tumor accumulation and poor cytosolic delivery to activate innate immune sensors. Here, we report a liponanogel (LNG)-based platform to address these challenges. The immunostimulatory LNG consists of an ionizable lipid shell coating a nanogel made of hyaluronic acid (HA), Mn 2+ and pIC, which is denoted as LNG-Mn-pIC (LMP). The protonation of internal HA within acidic endosomes increases the endosomal membrane permeability and facilitates the cytosolic delivery of pIC. Moreover, Mn 2+ , previously reported to activate the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, synergizes with pIC to activate innate immune cells. Remarkably, intravenously injected LMP significantly induces tumor vasculature disruption and tumor cell apoptosis in an innate immune activation-dependent manner, facilitating the LMP delivery into tumors and leading to enhanced antitumor immunity that potently inhibits or even completely regresses the established tumors. In summary, this immunostimulatory LNG platform not only serves as a useful tool to uncover the immune activation-enhanced drug delivery profile but also represents a broadly applicable platform for effective cancer immunotherapy., Competing Interests: Declaration of competing interest A patent application (2023103082977) has been filed based on the findings described in the manuscript, with R.K. and X. L. as inventors., (Copyright © 2024. Published by Elsevier B.V.)

Dendritic cells (DCs) within the tumor microenvironment (TME) have an insufficient capacity to activate T cells through antigen presentation. Furthermore, the programmed cell-death ligand 1 (PD-L1), abundantly expressed on tumor-associated DCs, binds the programmed cell-death 1 (PD-1)-positive T cells and suppresses their immune function. The binding of PD-L1 to CD80 (B7.1) on the same DC via cis -interactions further prevents T cell costimulation through CD28. Here, we present a strategy to simultaneously promote antigen cross-presentation and block the inhibitory interactions of PD-L1 on DCs to amplify T cell-mediated antitumor responses within the TME. Mesoporous silica nanoparticles (MSNPs) were loaded with clotrimazole (CLT) to boost MHC II-mediated antigen presentation by DCs, surface-modified with mannose to target CD206 on DCs, and then decorated with PD-L1 binding peptide (PDL1bp) to block PD-L1-mediated interactions. PDL1bp was cleaved from the mannosylated and CLT-loaded MSNPs (MSNP-MaN/CLT) under conditions simulating the TME and tethered to PD-L1 to reverse CD80 sequestration on DC2.4 cells. The blocking of PD-L1 by PDL1bp-decorated NPs (MSNP-MaN-PDL1bp) increased the cellular interactions between DC2.4 and EL4 T cells and the amount of IL-2 secretion. The MSNP-MaN/CLT were taken up rapidly by DC2.4 cells, promoted MHC II presentation of hen egg lysozyme (HEL), and increased IL-2 production from HEL antigen-primed 3A9 T cells, which was further enhanced by PDL1bp. In vivo investigation revealed that administration of the CLT-loaded and PDL1bp-functionalized MSNPs remarkably inhibited subcutaneous B16-F10 melanoma tumor growth when compared with anti-PD-L1 therapy. MSNP-MaN-PDL1bp/CLT treatment upregulated the levels of effector molecules such as granzyme B and proinflammatory cytokines (IFNγ and INFα) in the tumor tissue, indicating antitumoral T cell responses. This strategy of utilizing nanoparticles to trigger DC activation while promoting T cell stimulation can be used to amplify the antitumor T cell responses and represents a promising alternative to anti-PD-L1 immunotherapy.

Erbin is an adapter protein that interacts with the v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 (ERBB2) in epithelial cells. Erbin plays an important role in various signaling pathways, including cell proliferation, apoptosis, and autophagy. Additionally, Erbin is implicated in the pathogenesis and progression of sepsis and various cancers, including breast cancer, acute myeloid leukemia (AML), hepatocellular carcinoma (HCC), and colorectal cancer (CRC). A recent study shows that loss of Erbin increases the release of acyl-carnitine (Acar) through abolishing interaction with prothrombotic protein endothelial cell-specific adhesion molecule (ESAM), promotes mitochondrial oxidative phosphorylation in B cells, and ultimately suppresses lung metastasis of CRC. Accordingly, Erbin provides us with a new potential treatment for tumor metastasis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Qiu, Tan, Yan and Luo.)

Paraneoplastic neurological syndromes (PNS) are rare autoimmune disorders triggered by the presence of a cancer. The autoimmunity is herein directed against proteins expressed both in the tumor and in the nervous system, namely the onconeural antigens, against which are directed specific autoantibodies, each of them characterizing a neurological syndrome. The mechanisms of the immune tolerance breakdown in PNS leading to the production of specific autoantibodies directed against the nervous system and leading to the immune attack begins to be explained. Each syndrome is associated with a specific histo-molecular subtype of tumor suggesting a link between the PNS genesis and oncogenesis. The expression of the onconeural antigen by these tumors is insufficient to explain the immune tolerance breakdown. In some PNS tumors, alterations of the antigen have been identified: mutations, gene copy number variation and overexpression of transcript and protein. But in others PNS, no such molecular alterations of the onconeural antigens have been demonstrated. In these cases, other mechanisms of neoantigen generation that may be involved remain to be deciphered. Cancer outcomes of PNS tumors are also characterized by the high frequency of lymph node metastasis at diagnosis. At the primary tumor site, the antitumor immune reaction seems to be particularly intense and characterized by a prominence of B-cell and Ig-secreting plasma cells that may generate the autoantibody secretion. The immune control mechanisms leading to such organization of the immune attack are not known to date. Renewed research efforts are thus needed to better understand the mechanism of immune tolerance breakdown in each PNS and determine potential targets to meet the therapeutic challenges posed by these rare disorders., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Lysosome-targeting chimera (LYTAC) shows great promise for protein-based therapeutics by targeted degradation of disease-associated membrane or extracellular proteins, yet its efficiency is constrained by the limited binding affinity between LYTAC reagents and designated proteins. Here, we established a programmable and multivalent LYTAC system by tandem assembly of DNA into a high-affinity protein degrader, a heterodimer aptamer nanostructure targeting both pathogenic membrane protein and lysosome-targeting receptor (insulin-like growth factor 2 receptor, IGF2R) with adjustable spatial distribution or organization pattern. The DNA-based multivalent LYTACs showed enhanced efficacy in removing immune-checkpoint protein programmable death-ligand 1 (PD-L1) and vascular endothelial growth factor receptor 2 (VEGFR2) in tumor cell membrane that respectively motivated a significant increase in T cell activity and a potent effect on cancer cell growth inhibition. With high programmability and versatility, this multivalent LYTAC system holds considerable promise for realizing protein therapeutics with enhanced activity.

Gasdermin-mediated inflammatory cell death (pyroptosis) can activate protective immunity in immunologically cold tumors. Here, we performed a high-throughput screen for compounds that could activate gasdermin D (GSDMD), which is expressed widely in tumors. We identified 6,7-dichloro-2-methylsulfonyl-3-N-tert-butylaminoquinoxaline (DMB) as a direct and selective GSDMD agonist that activates GSDMD pore formation and pyroptosis without cleaving GSDMD. In mouse tumor models, pulsed and low-level pyroptosis induced by DMB suppresses tumor growth without harming GSDMD-expressing immune cells. Protection is immune-mediated and abrogated in mice lacking lymphocytes. Vaccination with DMB-treated cancer cells protects mice from secondary tumor challenge, indicating that immunogenic cell death is induced. DMB treatment synergizes with anti-PD-1. DMB treatment does not alter circulating proinflammatory cytokine or leukocyte numbers or cause weight loss. Thus, our studies reveal a strategy that relies on a low level of tumor cell pyroptosis to induce antitumor immunity and raise the possibility of exploiting pyroptosis without causing overt toxicity., Competing Interests: Declaration of interests H.W. and J.L. are co-founders of Ventus Therapeutics. H.W., J.L., P.F., G.D., J.J.H., S.M.V., Y.Z., H.Z., and M.S. have filed an invention disclosure on DMB’s antitumor effect. H.W., J.L., P.F., J.J.H., S.M.V., and H.Z. have filed an invention disclosure on DMB analogs from this study., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Pyroptosis, an inflammatory form of cell death, promotes the release of immunogenic substances and stimulates immune cell recruitment, a process, which could turn cold tumors into hot ones. Thus, instigating pyroptosis in triple-negative breast cancer (TNBC) serves as a viable method for restoring antitumor immunity. We analyzed the effects of Histone Deacetylase Inhibitors (HDACi) on TNBC cells using the Cell Counting Kit-8 and colony formation assay. Apoptosis and lactate dehydrogenase (LDH) release assays were utilized to determine the form of cell death. The pyroptotic executor was validated by quantitative real-time polymerase chain reaction and western blot. Transcriptome was analyzed to investigate pyroptosis-inducing mechanisms. A subcutaneously transplanted tumor model was generated in BALB/c mice to evaluate infiltration of immune cells. HDACi significantly diminished cell proliferation, and pyroptotic "balloon"-like cells became apparent. HDACi led to an intra and extracellular material exchange, signified by the release of LDH and the uptake of propidium iodide. Among the gasdermin family, TNBC cells expressed maximum quantities of GSDME, and expression of GSDMA, GSDMB, and GSDME were augmented post HDACi treatment. Pyroptosis was instigated via the activation of the caspase 3-GSDME pathway with the potential mechanisms being cell cycle arrest and altered intracellular REDOX balance due to aberrant glutathione metabolism. In vivo experiments demonstrated that HDACi can activate pyroptosis, limit tumor growth, and escalate CD8+ lymphocyte and CD11b+ cell infiltration along with an increased presence of granzyme B in tumors. HDACi can instigate pyroptosis in TNBC, promoting infiltration of immune cells and consequently intensifying the efficacy of anticancer immunity., (© 2024 Wiley Periodicals LLC.)

Unravelling the mechanisms for the immunosuppressive tumor microenvironment and developing corresponding therapeutic strategies are of great importance to improve the cancer immunotherapy. This study has revealed that there are abundant senescent cells accumulated in the colon cancer tissue, which contributes greatly to the immunosuppressive microenvironment. Oral delivery of Dasatinib and Quercetin (D+Q) eliminates the senescent cells with compromised efficiency due to the poor tumor penetration and short half-life. To improve the efficacy of senescent cell clearance, this work has developed an extracellular vesicle (EV) based senolytic strategy. The engineered senolytic EVs have anti-GPNMB (a senescent cell surface marker) displayed on the surface and D+Q loaded on the membrane. In a syngeneic mouse model, senolytic EVs efficiently and selectively eradicate the senescent cells and in turn unleashes the antitumor immunity. With the antitumor immunity boosted, cancer growth is inhibited and the survival is prolonged. In summary, this work has illuminated that senescent cells contribute to the immunosuppressive microenvironment in colon cancer and proposes a novel strategy to conquer the problem by EV-based senolytics., (© 2024 Wiley‐VCH GmbH.)

Loss of phosphatase and tensin homolog (PTEN) has been linked to an immunosuppressive tumor microenvironment, but its underlying mechanisms remain largely enigmatic. Here, we report that PTEN can be secreted by the transmembrane emp24 domain-containing protein 10 (TMED10)-channeled protein secretion pathway. Inhibiting PTEN secretion from tumor cells contributes to immunosuppression and impairs the tumor-suppressive role of PTEN, while intratumoral injection of PTEN protein promotes antitumor immunity and suppresses tumor growth in mice. Mechanistically, extracellular PTEN binds to the plexin domain-containing protein 2 (PLXDC2) on macrophages, triggering subsequent activation of JAK2-STAT1 signaling, which switches tumor-associated macrophages (TAMs) from the immunosuppressive to inflammatory phenotype, leading to enhanced activation of CD8 + T and natural killer cells. Importantly, PTEN treatment also enhances the therapeutic efficacy of anti-PD-1 treatment in mice and reverses the immune-suppressive phenotype of patient-derived primary TAMs. These data identify a cytokine-like role of PTEN in immune activation and tumor suppression and demonstrate the therapeutic potential for extracellular administration of PTEN in cancer immunotherapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: The role of zinc (Zn) in tumor development and immune modulation has always been paradoxical. This study redefines our understanding of the impact of Zn on cancer progression and therapeutic strategies., Methods: We investigated the effects of dietary Zn levels on tumor progression and immune responses. This included examining the impact of both high and deficient dietary Zn, as well as Zn chelation, on tumor growth and immune cell populations. Specifically, we analyzed the frequency of Foxp3 + regulatory T-cells (Tregs) and identified the role of FOXO1 in Zn-mediated effects on Tregs. Additionally, we explored the therapeutic potential of clioquinol (CQ) in enhancing α -PD-1 immunotherapy responses, particularly in melanoma., Results: Our findings show that high dietary Zn promotes tumor progression by fostering a protumorigenic environment mediated by T cells. Increased Zn intake was found to facilitate tumor progression by increasing Foxp3 + Treg frequency. In contrast, deficiency in dietary Zn and chelation of tissue Zn emerged as potent drivers of antitumor immunity. We pinpointed FOXO1 as the master regulator governing the influence of Zn on Tregs., Discussion: These results reveal a novel mechanistic insight into how Zn influences tumor progression and immune regulation. The identification of FOXO1 as a key regulator opens new avenues for understanding the role of Zn in cancer biology. Furthermore, we introduce a promising therapeutic approach by showing that administering clioquinol (CQ) significantly enhances α -PD-1 immunotherapy response, particularly in melanoma. These revelations transform our comprehension of the multifaceted role of Zn in tumorigenesis and immune regulation, highlighting innovative possibilities for cancer therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Narayan, Dalal, Rizvi and Awasthi.)

The preferable antigen delivery profile accompanied by sufficient adjuvants favors vaccine efficiency. Mitochondria, which feature prokaryotic characteristics and contain various damage-associated molecular patterns (DAMPs), are easily taken up by phagocytes and simultaneously activate innate immunity. In the current study, we established a mitochondria engineering platform for generating antigen-enriched mitochondria as cancer vaccine. Ovalbumin (OVA) and tyrosinase-related protein 2 (TRP2) were used as model antigens to synthesize fusion proteins with mitochondria-localized signal peptides. The lentiviral infection system was then employed to produce mitochondrial vaccines containing either OVA or TRP2. Engineered OVA- and TRP2-containing mitochondria (OVA-MITO and TRP2-MITO) were extracted and evaluated as potential cancer vaccines. Impressively, the engineered mitochondria vaccine demonstrated efficient antitumor effects when used as both prophylactic and therapeutic vaccines in murine tumor models. Mechanistically, OVA-MITO and TRP2-MITO potently recruited and activated dendritic cells (DCs) and induced a tumor-specific cell-mediated immunity. Moreover, DC activation by mitochondria vaccine critically involves TLR2 pathway and its lipid agonist, namely, cardiolipin derived from the mitochondrial membrane. The results demonstrated that engineered mitochondria are natively well-orchestrated carriers full of immune stimulants for antigen delivery, which could preferably target local dendritic cells and exert strong adaptive cellular immunity. This proof-of-concept study established a universal platform for vaccine construction with engineered mitochondria bearing alterable antigens for cancers as well as other diseases., (© 2024. The Author(s).)

Pyroptosis, a newly characterized type of inflammatory programmed cell death (PCD), is usually triggered by multiple inflammasomes which can recognize different danger or damage-associated molecular patterns (DAMPs), leading to the activation of caspase-1 and the cleavage of gasdermin D (GSDMD). Gasdermin family pore-forming proteins are the executers of pyroptosis and are normally maintained in an inactive state through auto-inhibition. Upon caspases mediated cleavage of gasdermins, the pro-pyroptotic N-terminal fragment is released from the auto-inhibition of C-terminal fragment and oligomerizes, forming pores in the plasma membrane. This results in the secretion of interleukin (IL)-1β, IL-18, and high-mobility group box 1 (HMGB1), generating osmotic swelling and lysis. Current therapeutic approaches including chemotherapy, radiotherapy, molecularly targeted therapy and immunotherapy for lung cancer treatment efficiently force the cancer cells to undergo pyroptosis, which then generates local and systemic antitumor immunity. Thus, pyroptosis is recognized as a new therapeutic regimen for the treatment of lung cancer. In this review, we briefly describe the signaling pathways involved in pyroptosis, and endeavor to discuss the antitumor effects of pyroptosis and its potential application in lung cancer therapy, focusing on the contribution of pyroptosis to microenvironmental reprogramming and evocation of antitumor immune response., (© 2024 Wiley Periodicals LLC.)

Enhancing the antitumor immune response and targeting ability of oncolytic viruses will improve the effect of tumor immunotherapy. Through infecting neural stem cells (NSCs) with a capsid dual-modified oncolytic adenovirus (CRAd), we obtained and characterized the "oncolytic extracellular vesicles" (CRAdEV) with improved targeted infection and tumor killing activity compared with CRAd. Both ex vivo and in vivo studies revealed that CRAdEV activated innate immune cells and importantly enhanced the immunomodulatory effect compared to CRAd. We found that CRAdEV effectively increased the number of DCs and activated CD4 + and CD8 + T cells, significantly increased the number and activation of B cells, and produced higher levels of tumor-specific antibodies, thus eliciting enhanced antitumor activity compared with CRAd in a B16 xenograft immunocompetent mice model. This study provides a novel approach to oncolytic adenovirus modification and demonstrates the potential of "oncolytic extracellular vesicles" in antitumor immunotherapy.

With the advancing comprehension of immunology, an increasing number of immunotherapies are being explored and implemented in the field of cancer treatment. The cGAS-STING pathway, a crucial element of the innate immune response, has been identified as pivotal in cancer immunotherapy. We evaluated the antitumor effects of Schisandra chinensis lignan component Schisandrin C (SC) in 4T1 and MC38 tumor-bearing mice, and studied the enhancing effects of SC on the cGAS-STING pathway and antitumor immunity through RNA sequencing, qRT-PCR, and flow cytometry. Our findings revealed that SC significantly inhibited tumor growth in models of both breast and colon cancer. This suppression of tumor growth was attributed to the activation of type I IFN response and the augmented presence of T cells and NK cells within the tumor. Additionally, SC markedly promoted the cGAS-STING pathway activation induced by cisplatin. In comparison to cisplatin monotherapy, the combined treatment of SC and cisplatin exhibited a greater inhibitory effect on tumor growth. The amplified chemotherapeutic efficacy was associated with an enhanced type I IFN response and strengthened antitumor immunity. SC was shown to reduce tumor growth and increase chemotherapy sensitivity by enhancing the type I IFN response activation and boosting antitumor immunity, which enriched the research into the antitumor immunity of S. chinensis and laid a theoretical basis for its application in combating breast and colon cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Yang, Zhan, Zhao, Shi, Liu, Wei, Li, Hou, Mu, Chen, Zheng, Wang, Wei, Xiao and Bai.)

This study investigated the synergistic potential of an oncolytic herpes simplex virus armed with interleukin 12 (VT1092M) in combination with immune checkpoint inhibitors for enhancing antitumor responses. The potential of this combination treatment to induce systemic antitumor immunity was assessed using bilateral subcutaneous tumor and tumor re-challenge mouse models. The antitumor efficacy of various OV and ICI treatment combinations and the underlying mechanisms were explored through diverse analytical techniques, including flow cytometry and RNA sequencing. Using VT1092M, either alone or in combination with an anti-PD-L1 antibody, significantly reduced the sizes of both the injected and untreated abscopal tumors in a bilateral tumor mouse model. The combination therapy demonstrated superior antitumor efficacy to the other treatment conditions tested, which was accompanied by an increase in T cell numbers and CD8 + T cell activation. Results from the survival and tumor re-challenge experiments showed that the combination therapy elicited long-term, tumor-specific immune responses, which were associated with tumor clearance and prolonged survival. Immune cell depletion assays identified CD8 + T cells as the crucial mediators of systemic antitumor immunity during combination therapy. In conclusion, the combination of VT1092M and PD-L1 blockade emerged as a potent inducer of antitumor immune responses, surpassing the efficacy of each monotherapy. This synergistic approach holds promise for achieving robust and sustained antitumor immunity, with potential implications for preventing tumor metastasis in patients with cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

The prognosis of oral squamous cell carcinoma (OSCC) largely depends on the control of lymph node metastases. We evaluate the therapeutic efficacy of G47Δ, a third-generation oncolytic herpes simplex virus type 1 (HSV-1), in mouse tongue cancer models. Intratumoral injection with G47Δ prolonged the survival in all orthotopic models investigated. In both athymic and immunocompetent models, G47Δ injected into the tongue cancer swiftly traffics to the draining cervical lymph nodes and suppresses lymph node metastases. In the immunocompetent KLN205-MUC1 model, in which the metastatic cascade that tongue cancer patients commonly experience is reproduced, intratumoral G47Δ injection even immediately prior to a tumor resection prolonged survival. Cervical lymph nodes 18 h after G47Δ treatment showed the presence of G47Δ infection and an increase in CD69-positive cells, indicating an immediate activation of T cells. Furthermore, G47Δ injected directly into enlarged metastatic lymph nodes significantly prolonged the survival at an advanced stage. Whereas intratumorally injected oncolytic HSV-1 does not readily circulate in the blood stream, G47Δ is shown to traffic in the lymphatics swiftly. The use of G47Δ can lead to entirely new treatment strategies for tongue cancer and other OSCC at all clinical stages.

Abstract Tumor resistance to apoptosis and the immunosuppressive tumor microenvironment are two major contributors to poor therapeutic responses during cancer intervention. Pyroptosis, a lytic and inflammatory programmed cell death pathway distinct from apoptosis, has subsequently sparked notable interest among cancer researchers for its potential to be clinically harnessed and to address these problems. Recent evidence indicates that pyroptosis induction in tumor cells leads to a robust inflammatory response and marked tumor regression. Underlying its antitumor effect, pyroptosis is mediated by pore-forming gasdermin proteins that facilitate immune cell activation and infiltration through their release of pro-inflammatory cytokines and immunogenic material following cell rupture. Considering its inflammatory nature, however, aberrant pyroptosis may also be implicated in the formation of a tumor supportive microenvironment, as evidenced by the upregulation of gasdermin proteins in certain cancers. In this review, the molecular pathways leading to pyroptosis are introduced, followed by an overview of the seemingly entangled links between pyroptosis and cancer. We describe what is known regarding the impact of pyroptosis on anticancer immunity and give insight into the potential of harnessing pyroptosis as a tool and applying it to novel or existing anticancer strategies.

Tumor immunotherapy mainly relies on activating the immune system to achieve antitumor treatment. However, the present tumor immunotherapy used in the clinic showed low treatment efficacy with high systematic toxicity. To overcome the shortcomings of traditional drugs for immunotherapy, a series of antitumor immunotherapies based on nanomaterials have been developed to enhance the body’s antitumor immune response and reduce systematic toxicity. Due to the noninvasiveness, remote controllability, and high temporal and spatial resolution of light, photocontrolled nanomaterials irradiated by excitation light have been widely used in drug delivery and photocontrolled switching. This review aims to highlight recent advances in antitumor immunotherapy based on photocontrolled nanomaterials. We emphasized the advantages of nanocomposites for antitumor immunotherapy and highlighted the latest progress of antitumor immunotherapy based on photoactivated nanomaterials. Finally, the challenges and future prospects of light-activated nanomaterials in antitumor immunity are discussed.

Background: Although current immunotherapies have achieved some successes for hepatocellular carcinoma (HCC) patients, their benefits are limited for most HCC patients. Therefore, the identification of biomarkers for promoting immunotherapeutic responses in HCC is urgently needed.Methods: Using the TCGA HCC cohort, we investigated correlations of various molecular features with antitumor immune signatures (CD8+ T cell infiltration and cytolytic activity) and an immunosuppressive signature (PD-L1 expression) in HCC. These molecular features included mRNAs, microRNAs (miRNAs), long non-coding RNAs (lncRNAs), proteins, and pathways.Results: We found that the mutations of several oncogenes and tumor suppressor genes significantly correlated with reduced antitumor immune signatures, including TTN, CTNNB1, RB1, ZFHX4, and TP53. It indicates that these genes’ mutations may inhibit antitumor immune responses in HCC. Four proteins (Syk, Lck, STAT5, and Caspase-7) had significant positive expression correlations with CD8+ T cell enrichment, cytolytic activity, and PD-L1 expression in HCC. It suggests that these proteins’ expression could be useful biomarkers for the response to immune checkpoint inhibitors Similiarly, we identified other types of biomarkers potentially useful for predicting the response to ICIs, including miRNAs (hsa-miR-511-5p, 150-3p, 342-3p, 181a-3p, 625-5p, 4772-3p, 155-3p, 142-5p, 142-3p, 155-5p, 625-3p, 1976, 7702), many lncRNAs, and pathways (apoptosis, cytokine-cytokine receptor interaction, Jak-STAT signaling, MAPK signaling, PI3K-AKT signaling, HIF-1 signaling, ECM receptor interaction, focal adhesion, and estrogen signaling). Further, tumor mutation burden showed no significant correlation with antitumor immunity, while tumor aneuploidy levels showed a significant negative correlation with antitumor immunity.Conclusion: The molecular features significantly associated with HCC immunity could be predictive biomarkers for immunotherapeutic responses in HCC patients. They could also be potential intervention targets for boosting antitumor immunity and immunotherapeutic responses in HCC.

To overcome the hurdles of immunotherapy, we investigated whether calcipotriol, a synthetic vitamin D analog, could overcome the immune evasion of glioblastoma multiforme (GBM) by modulating immune responses and the immunosuppressive tumor microenvironment. Administration of calcipotriol considerably reduced tumor growth. Both in vivo and in vitro studies revealed that CD8+T and natural killer (NK) cell gene signatures were enriched and activated, producing high levels of IFN-γ and granzyme B. In contrast, regulatory T cells (Treg) were significantly reduced in the calcipotriol-treated group. The expression of CD127, the receptor for thymic stromal lymphopoietin (TSLP), is elevated in CD4+T cells and potentially supports T-cell priming. Depleting CD4+T cells, but not NK or CD8+T cells, completely abrogated the antitumor efficacy of calcipotriol. These data highlight that the calcipotriol/TSLP/CD4+T axis can activate CD8+T and NK cells with a concomitant reduction in the number of Tregs in GBM. Therefore, calcipotriol can be a novel therapeutic modality to overcome the immune resistance of GBM by converting immunologically “cold” tumors into “hot” tumors. Data availability: Data are available upon reasonable request. The RNA-seq dataset comparing the transcriptomes of control and calcipotriol-treated GL261 tumors is available from the corresponding author upon request.

The variability and heterogeneity of tumor antigens and the tumor-driven development of immunosuppressive mechanisms leading to tumor escape from established immunological surveillance. Here, the tumor cells were genetically modified to achieve an inducible overexpression of the N-terminal domain of gasdermin D (GSDMD-NT) and effectively cause pyroptosis under a strict control. Pyroptotic tumor cells release damage-associated molecular patterns (DAMPs) and inflammatory cytokines to promote the maturation and migration of bone marrow-derived dendritic cells (BMDCs). Furthermore, local tumor delivery, and preventive or therapeutic subcutaneous immunization of the modified cells, followed by the induction of GSDMD-NT expression, significantly stimulated both the systemic and local responses of antitumor immunity, and reprogrammed the tumor microenvironment, leading to the dramatic suppression of tumor growth in mice. This study has explored the application potency of inducing the pyroptosis of tumor cells in the field of tumor immunotherapy, especially for developing a new and promising personalized tumor vaccine.

Metastasis, a primary cause of death in patients with malignancies, is promoted by intrinsic changes in both tumor and non-malignant cells in the tumor microenvironment (TME). As major components of the TME, tumor-associated neutrophils (TANs) promote tumor progression and metastasis through communication with multiple growth factors, chemokines, inflammatory factors, and other immune cells, which together establish an immunosuppressive TME. In this review, we describe the potential mechanisms by which TANs participate in tumor metastasis based on recent experimental evidence. We have focused on drugs in chemotherapeutic regimens that target TANs, thereby providing a promising future for cancer immunotherapy.

Cancer is a major public health problem that threatens human life worldwide. In recent years, immunotherapy has made great progress in both clinical and laboratory research. But the high heterogeneity and dynamics of tumors makes immunotherapy not suitable for all cancers. Dietary polyphenols have attracted researchers' attention due to their ability to induce cancer cell pyroptosis and to regulate the tumor immune microenvironment (TIME). This review expounds the regulation of dietary polyphenols and their new forms on cancer cell pyroptosis and the TIME. These dietary polyphenols include curcumin (CUR), resveratrol (RES), epigallocatechin gallate (EGCG), apigenin, triptolide (TPL), kaempferol, genistein and moscatilin. New forms of dietary polyphenols refer to their synthetic analogs and nano-delivery, liposomes. Studies in the past decade are included. The result shows that dietary polyphenols induce pyroptosis in breast cancer cells, liver cancer cells, oral squamous cells, carcinoma cells, and other cancer cells through different pathways. Moreover, dietary polyphenols exhibit great potential in the TIME regulation by modulating the programmed cell death protein 1(PD-1)/programmed death-ligand 1 (PD-L1) axis, enhancing antitumor immune cells, weakening the function and activity of immunosuppressive cells, and targeting tumor-associated macrophages (TAMs) to reduce their tumor infiltration and promote their polarization toward the M1 type. Dietary polyphenols are also used with radiotherapy and chemotherapy to improve antitumor immunity and shape a beneficial TIME. In conclusion, dietary polyphenols induce cancer cell pyroptosis and regulate the TIME, providing new ideas for safer cancer cures.

Background: NRAS wildtype melanoma accounts for approximately 80% of melanomas. Previous studies have shown that NRAS wildtype melanoma had higher response rates and better prognoses than NRAS-mutant patients following immunotherapy, while as major actors in tumor cells and tumor microenvironment (TME), the association between NOTCH family genes and response to immunotherapy in NRAS wildtype melanoma remains indistinct. Objective: We aim to explore whether NOTCH family gene variation is associated with genomic factors in immune checkpoint inhibitor (ICI) response in NRAS wildtype melanoma and with clinical results in these patients. Method: This research used genomic data of 265 NRAS wildtype ICI-pretreatment samples from five ICI-treated melanoma cohorts to analyze the relationship between NOTCH family gene mutation and the efficacy of ICI therapy. Results: NRAS wildtype melanomas with NOTCH4-Mut were identified to be associated with prolonged overall survival (OS) in both the discovery (HR: 0.30, 95% CI: 0.11–0.83, P = 0.01) and validation cohorts(HR: 0.21, 95% CI: 0.07–0.68, P = 0.003). Moreover, NOTCH4-Mut melanoma had a superior clinical response in the discovery cohort (ORR, 40.0% vs 13.11%, P = 0.057) and validation cohort (ORR, 68.75% vs 30.07%, P = 0.004). Further exploration found that NOTCH4-Mut tumors had higher tumor mutation burden (TMB) and tumor neoantigen burden (TNB) (P <0.05). NOTCH4-Mut tumors had a significantly increased mutation in the DNA damage response (DDR) pathway. Gene set enrichment analysis revealed NOTCH4-Mut tumor enhanced anti-tumor immunity. Conclusion: NOTCH4 mutation may promote tumor immunity and serve as a biomarker to predict good immune response in NRAS wildtype melanoma and guide immunotherapeutic responsiveness. [ABSTRACT FROM AUTHOR]

Cancer driven by somatic mutations may express neoantigens that can trigger T-cell immune responses. Since T-cell receptor (TCR) repertoires play critical roles in anti-tumor immune responses for oncology, next-generation sequencing (NGS) was used to profile the hypervariable complementaritydetermining region 3 (CDR3) of the TCR-beta chain in peripheral blood samples from 68 gastric cancer patients and 49 healthy controls. We found that most hyper-expanded CDR3 are individual-specific, and the gene usage of TRBV3-1 is more frequent in the tumor group regardless of tumor stage than in the healthy control group. We identified 374 hyper-expanded tumor-specific CDR3, which may play a vital role in anti-tumor immune responses. The patients with stage IV gastric cancer have higher EBV-specific CDR3 abundance than the control. In conclusion, analysis of the peripheral blood TCR repertoires may provide the biomarker for gastric cancer prognosis and guide future immunotherapy. [ABSTRACT FROM AUTHOR]

Recent studies suggest that highly activated, polyfunctional CD4+ T cells are incredibly effective in strengthening and sustaining overall host antitumor immunity, promoting tumor-specific CD4+ T-cell responses and effectively enhancing antitumor immunity by immunotherapy. Previously, we developed a novel cryo-thermal therapy for local tumor ablation and achieved long-term survival rates in several tumor models. It was discovered that cryo-thermal therapy remodeled the tumor microenvironment and induced an antigen-specific CD4+ T-cell response, which mediated stronger antitumor immunity in vivo. In this study, the phenotype of bulk T cells in spleen was analyzed by flow cytometry after cryo-thermal therapy and both CD4+ Th1 and CD8+ CTL were activated. In addition, by using T-cell depletion, isolation, and adoptive T-cell therapy, it was found that cryo-thermal therapy induced Th1-dominant CD4+ T cells that directly inhibited the growth of tumor cells, promoted the maturation of MDSCs via CD4+ T-cell-derived IFN-γ and enhanced the cytotoxic effector function of NK cells and CD8+ T cells, and promoted the maturation of APCs via cell-cell contact and CD4+ T-cell-derived IFN-γ. Considering the multiple roles of cryo-thermal-induced Th1-dominant CD4+ T cells in augmenting antitumor immune memory, we suggest that local cryo-thermal therapy is an attractive thermo-immunotherapy strategy to harness host antitumor immunity and has great potential for clinical application. [ABSTRACT FROM AUTHOR]

In situ tumor vaccine is a potential cancer therapy due to their advantages in induction of antitumor immune responses. Oncolytic virotherapy utilizes natural or engineered oncolytic viruses to kill tumors selectively, representing a promising in situ tumor vaccine for cancer immunotherapy. In addition to direct oncolysis, oncolytic viruses elicit potent and durable antitumor immune responses by induction of immunogenic cell death of tumors. Membrane protein CD47 overexpressed on tumor cells engages in "don't eat me" signal that prevents macrophages from engulfing tumor cells. CD47-targeting agents have been tested via preclinical and clinical trials. As potential tumor vaccine vectors, oncolytic viruses can be engineered to express anti-CD47 antibodies to induce potentiated tumor killing. Therefore, we developed an adenovirus-based tumor vaccine loaded with a CD47-targeting nanobody fused with the IgG2a Fc protein. B16-F10 melanoma, A20 lymphoma, and 4T1 breast cancer models in immunocompetent mice were established to evaluated in vivo antitumor efficacy of in situ tumor vaccination. The tumor vaccine armed with a nanobody against CD47 induced durable suppression of the tumor and long-term survival of tumor-bearing mice, and also elevated the number of tumor-infiltrating immune cells with an activated immunophenotype, suggesting that it could remodel the tumor immune microenvironment. Systemic antitumor effects and immune memory were also observed in immunocompetent mice following in situ vaccination with the anti-CD47 tumor vaccines; tumorigenesis was completely inhibited in these mice after tumor re-challenge. The recombinant anti-CD47 tumor vaccine has an effectual antitumor activity and may be a promising antitumor agent. [ABSTRACT FROM AUTHOR]

Cancer cachexia syndrome (CCS) is a multifactorial metabolic syndrome affecting a significant proportion of patients. CCS is characterized by progressive weight loss, alterations of body composition and a systemic inflammatory status, which exerts a major impact on the host's innate and adaptive immunity. Over the last few years, the development of immune checkpoint inhibitors (ICIs) transformed the treatment landscape for a wide spectrum of malignancies, creating an unprecedented opportunity for long term remissions in a significant subset of patients. Early clinical data indicate that CCS adversely impairs treatment outcomes of patients receiving ICIs. We herein reviewed existing evidence on the potential links between the mechanisms that promote the catabolic state in CCS and those that impair the antitumor immune response. We show that the biological mediators and processes leading to the development of CCS may also participate in the modulation and the sustainment of an immune suppressive tumor microenvironment and impaired anti-tumor immunity. Moreover, we demonstrate that the deregulation of the host's metabolic homeostasis in cancer cachexia is associated with resistance to ICIs. Further research on the interrelation between cancer cachexia and anti-tumor immunity is required for the effective management of resistance to immunotherapy in this specific but large subgroup of ICI treated individuals. [ABSTRACT FROM AUTHOR]

Despite an ever-increasing appreciation of how protein-coding genes shape immune responses, the molecular underpinnings of immune regulation remain incompletely understood. This incomplete picture impedes the development of more precise therapeutics and diagnostics for immune-mediated diseases. Long noncoding RNAs (lncRNAs) are versatile cell- and context-specific regulators of gene expression and cellular function. The number of lncRNA genes rivals that of protein-coding genes; however, comparatively little is known about their function. Even though the functions of most lncRNA genes are unknown, multiple lncRNAs have recently emerged as important immune regulators. Therefore, further unlocking the role of lncRNAs in the mammalian immune system coupled with their tissue-specific expression might lead to more precise therapeutics and diagnostics for immune disorders in general. Long noncoding RNAs (lncRNAs) are tissue- and context-specific modulators of immune cell development, differentiation, activation, and function. lncRNA molecular mechanisms are diverse and challenging to predict. lncRNAs impact on the outcomes of protective and pathogenic immune responses in a variety of diseases. lncRNA genes outnumber protein-coding genes, but comparatively few lncRNAs have been functionally or mechanistically characterized. Further unlocking the role of lncRNAs in immunity may lead to improved outcomes for diseases that are influenced by protective and pathogenic immune responses. [ABSTRACT FROM AUTHOR]

Ferroptosis is a type of programmed cell death dependent on iron and characterized by the accumulation of lipid peroxides. In this study, we explore the combination of a ferroptosis activator with an oncolytic vaccinia virus in tumor models. Erastin induced cell death in hepatoma, colon, and ovarian cancer cells, but not in melanoma cancer cells. Erastin, not the oncolytic vaccinia virus (OVV), induced the expression of key marker genes for ferroptosis in cancer cells. In hepatocellular carcinoma and colon cancer models, either erastin or OVV inhibited tumor growth, but a combination of the two yielded the best therapeutic effects, as indicated by inhibited tumor growth or regression and longer host survival. Immunological analyses indicate that erastin alone had little or no effect on systemic immunity or local immunity in the tumor. However, when combined with OV, erastin enhanced the number of activated dendritic cells and the activity of tumor-infiltrating T lymphocytes as indicated by an increase in IFN-γ+CD8+ and PD-1+CD8+ T cells. These results demonstrate that erastin can exert cytotoxicity on cancer cells via ferroptosis, but has little effect on immune activity by itself. However, when combined with an OVV, erastin promoted antitumoral immunity and efficacy by increasing the number of activated dendritic cells and promoting the activities of tumor specific CD8+ T cells in the tumor. [ABSTRACT FROM AUTHOR]