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For decades, lactate has been considered an innocuous bystander metabolite of cellular metabolism. However, emerging studies show that lactate acts as a complex immunomodulatory molecule that controls innate and adaptive immune cells' effector functions. Thus, recent advances point to lactate as an essential and novel signaling molecule that shapes innate and adaptive immune responses in the intestine and systemic sites. Here, we review these recent advances in the context of the pleiotropic effects of lactate in regulating diverse functions of immune cells in the tissue microenvironment and under pathological conditions. [ABSTRACT FROM AUTHOR]

The way of cell death can be roughly divided into two categories: cell necrosis and PCD(programmed cell death). Pyroptosis is a kind of PCD, its occurrence depends on the gasdermin protein family and it will produce inflammatory response. With constant research in recent years, more and more evidences show that pyroptosis is closely related to the occurrence and development of tumors. The treatment of tumors is a big problem worldwide. We focus on whether we can discover new potential tumor markers and new therapeutic targets from the mechanism. If we can understand the mechanism of pyroptosis and clear the relationship between pyroptosis and the development of tumors, this may provide a new reference for clinical cancer treatment. [ABSTRACT FROM AUTHOR]

The patient's hormonal context plays a crucial role in the outc ome of cancer. However, the association between thyroid disease and breast cancer risk remains unclear. We evaluated the effect of thyroid status on breast cancer growth a nd dissemination in an immunocompetent mouse model. For this, hyperthyroid and hypothyroid Balb/c mice were orthotopically inoculated with triple-negative breast cancer 4T1 cells. Tumors from hyperthyroid mice showed an increased growth rate and an immunosuppressive tumor microenvironment, characterized by increased IL-10 levels and decreased percentage of activated cytotoxic T cells. On the other hand, delayed tumo r growth in hypothyroid animals was associated with increased tumor infiltration of activated CD8+ cells and a high IFNγ/IL-10 ratio. Paradoxically, hypothyroid mice developed a higher number of lung metastasis than hyperthyroid animals. This was related to an increased secretion of tumor CCL2 and an immunosuppressive systemic environment, with increased proportion of regulatory T cells and IL-10 levels in spleens. A lower number of lung metastasis in hyperthyroid mice was related to the reduced presence of mesenchymal stem cells in tumors and metastatic sites. These animals also e xhibited decreased percentages of regulatory T lymphocytes and myeloid-derived suppressor cells in spleens but increased activated CD8+ cells and the IFNγ/IL-10 ratio. Therefore, thyroid hormones modulate the cellular and cytokine content of the breast tumor microenvironment. A better understanding of the mechanisms involved in these effects could be a starting point for the discovery of new therapeutic targets for breast c ancer. [ABSTRACT FROM AUTHOR]

The development of BCR-ABL1 tyrosine kinase inhibitors (TKIs) markedly improved the prognosis of patients with chronic myeloid leukemia (CML). Approximately 50% of patients who achieve deep molecular response (DMR) remain in treatment-free remission (TFR) even after discontinuation of TKIs. Although TKIs may achieve clinical "cure" after TKI treatment for specific periods, there are no reliable biomarkers for predicting the response to TKIs and the probability of TFR in CML. An increase in natural killer (NK) cells in the peripheral blood of TKI-treated CML patients is correlated with better outcomes, suggesting that TKIs induce antitumor NK cell immunity against CML cells. Killer immunoglobulin-like receptors (KIRs) are highly polymorphic NK cell receptors that play important roles in the regulation of immune responses. The identification of allelic polymorphisms of KIRs by next-generation sequencing uncovered novel aspects of KIRs. Here we summarize the current knowledge of the genetic and immunological aspects of KIRs and discuss the association between allelic polymorphisms of KIRs and TKI-treated CML. [ABSTRACT FROM AUTHOR]

In recent years, immunotherapy has proven to be an effective treatment against cancer. Cytotoxic T lymphocytes perform an important role in this anti-tumor immune response, recognizing cancer cells as foreign, through the presentation of tumor antigens by MHC class I molecules. However, tumors and metastases develop escape mechanisms for evading this immunosurveillance and may lose the expression of these polymorphic molecules to become invisible to cytotoxic T lymphocytes. In other situations, they may maintain MHC class I expression and promote immunosuppression of cytotoxic T lymphocytes. Therefore, the analysis of the expression of MHC class I molecules in tumors and metastases is important to elucidate these escape mechanisms. Moreover, it is necessary to determine the molecular mechanisms involved in these alterations to reverse them and recover the expression of MHC class I molecules on tumor cells. This review discusses the role and regulation of MHC class I expression in tumor progression. We focus on altered MHC class I phenotypes present in tumors and metastases, as well as the molecular mechanisms responsible for MHC-I alterations, emphasizing the mechanisms of recovery of the MHC class I molecules expression on cancer cells. The individualized study of the HLA class I phenotype of the tumor and the metastases of each patient will allow choosing the most appropriate immunotherapy treatment based on a personalized medicine. [ABSTRACT FROM AUTHOR]

Significance: Genomic instability, a hallmark of cancer, renders cancer cells susceptible to genomic stress from both endogenous and exogenous origins, resulting in the increased tendency to accrue DNA damage, chromosomal instability, or aberrant DNA localization. Apart from the cell autonomous tumor-promoting effects, genomic stress in cancer cells could have a profound impact on the tumor microenvironment. Recent Advances: Recently, it is increasingly appreciated that harnessing genomic stress could provide a promising strategy to revive antitumor immunity, and thereby offer new therapeutic opportunities in cancer treatment. Critical Issues: Genomic stress is closely intertwined with antitumor immunity via mechanisms involving the direct crosstalk with DNA damage response components, upregulation of immune-stimulatory/inhibitory ligands, release of damage-associated molecular patterns, increase of neoantigen repertoire, and activation of DNA sensing pathways. A better understanding of these mechanisms will provide molecular basis for exploiting the genomic stress to boost antitumor immunity. Future Directions: Future research should pay attention to the heterogeneity between individual cancers in the genomic instability and the associated immune response, and how to balance the toxicity and benefit by specifying the types, potency, and treatment sequence of genomic stress inducer in therapeutic practice. Antioxid. Redox Signal. 34, 1128–1150. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells are critical innate lymphocytes that can directly kill target cells without prior immunization. NK cell activation is controlled by the balance of multiple germline-encoded activating and inhibitory receptors. NK cells are a heterogeneous and plastic population displaying a broad spectrum of functional states (resting, activating, memory, repressed, and exhausted). In this review, we present an overview of the epigenetic regulation of NK cell-mediated antitumor immunity, including DNA methylation, histone modification, transcription factor changes, and microRNA expression. NK cell-based immunotherapy has been recognized as a promising strategy to treat cancer. Since epigenetic alterations are reversible and druggable, these studies will help identify new ways to enhance NK cell-mediated antitumor cytotoxicity by targeting intrinsic epigenetic regulators alone or in combination with other strategies. [ABSTRACT FROM AUTHOR]

Several studies have reported that tissue‐resident memory T cells (TRM cells) or tertiary lymphoid structures (TLSs) are associated with a good prognosis. The aim of this study was to clarify the association of TRM cells and TLSs in the tumor immune microenvironment in gastric cancer (GC). We performed immunohistochemical and immunofluorescence staining to detect the presence of CD103+ T cells and to assess the association between CD103+ T cells and TLSs. CD103+ T cells were observed in the tumor epithelium accompanied by CD8+ T cells and were associated with a better prognosis in GC. Furthermore, CD103+ T cells were located around TLSs, and patients with CD103high had more rich TLSs. Patients who had both CD103high cells and who were TLS‐rich had a better prognosis than patients with CD103low cells and who were TLS‐poor. Moreover, for patients who received PD‐1 blockade therapy, CD103high and TLS‐rich predicted a good response. Flow cytometry was performed to confirm the characteristics of CD103+CD8+ T cells and showed that CD103+CD8+ T cells in GC expressed higher levels of PD‐1, granzyme B, and interferon‐γ than CD103−CD8+ T cells. Our results suggested that CD103+CD8+ cells in GC are correlated with TLSs, resulting in enhanced antitumor immunity in GC. [ABSTRACT FROM AUTHOR]

The importance of trained immunity in antitumor immunity has been increasingly recognized, but the underlying metabolic regulation mechanisms remain incompletely understood. In this study, we find that squalene epoxidase (SQLE), a key enzyme in cholesterol synthesis, is required for β-glucan-induced trained immunity in macrophages and ensuing antitumor activity. Unexpectedly, the shunt pathway, but not the classical cholesterol synthesis pathway, catalyzed by SQLE, is required for trained immunity induction. Specifically, 24(S),25-epoxycholesterol (24(S),25-EC), the shunt pathway metabolite, activates liver X receptor and increases chromatin accessibility to evoke innate immune memory. Meanwhile, SQLE-induced reactive oxygen species accumulation stabilizes hypoxia-inducible factor 1α protein for metabolic switching into glycolysis. Hence, our findings identify 24(S),25-EC as a key metabolite for trained immunity and provide important insights into how SQLE regulates trained-immunity-mediated antitumor activity. [Display omitted] • Squalene epoxidase (SQLE) blockade inhibits β-glucan-induced trained immunity in macrophages • SQLE produces reactive oxygen species (ROS) in trained macrophages to promote glycolysis • SQLE-catalyzed 24(S),25-epoxycholesterol activates LXR to reprogram chromatin accessibility • SQLE is required for interferon production in trained macrophages to boost antitumor activity Liu et al. show that trained immunity in macrophages requires SQLE-catalyzed squalene epoxidation, which not only produces 24(S),25-epoxycholesterol for LXR activation and ensuing reprogramming of histone modification and chromatin accessibility but also generates ROS for glycolytic induction, extending a non-classical function of SQLE in regulating trained immunity. [ABSTRACT FROM AUTHOR]

The major histocompatibility complex class I (MHC class I)-mediated tumor antigen processing and presentation (APP) pathway is essential for the recruitment and activation of cytotoxic CD8+ T lymphocytes (CD8+ CTLs). However, this pathway is frequently dysregulated in many cancers, thus leading to a failure of immunotherapy. Here, we report that activation of the tumor-intrinsic Hippo pathway positively correlates with the expression of MHC class I APP genes and the abundance of CD8+ CTLs in mouse tumors and patients. Blocking the Hippo pathway effector Yes-associated protein/transcriptional enhanced associate domain (YAP/TEAD) potently improves antitumor immunity. Mechanistically, the YAP/TEAD complex cooperates with the nucleosome remodeling and deacetylase complex to repress NLRC5 transcription. The upregulation of NLRC5 by YAP/TEAD depletion or pharmacological inhibition increases the expression of MHC class I APP genes and enhances CD8+ CTL-mediated killing of cancer cells. Collectively, our results suggest a crucial tumor-promoting function of YAP depending on NLRC5 to impair the MHC class I APP pathway and provide a rationale for inhibiting YAP activity in immunotherapy for cancer. [Display omitted] • YAP/TEAD inhibits NLRC5 transcription to dampen MHC class I neoantigen presentation • The NuRD complex is required for the YAP/TEAD-repressed expression of MHC class I APP genes • Inhibition or depletion of YAP improves antitumor immunity through NLRC5-MHC class I axis Peng et al. show that the YAP/TEAD complex cooperates with the NuRD complex to repress NLRC5 transcription, thus impairing the MHC class I APP pathway and CD8+ CTL-mediated killing of cancer cells. They provide a rationale for inhibiting YAP activity in immunotherapy for cancer. [ABSTRACT FROM AUTHOR]

Glehnia littoralis is an edible plant with significant medicinal value. To further elucidate the potential functional components for developing antitumor agents or functional foods, the polysaccharides in this plant were investigated, and a homogeneous polysaccharide, GLP90-2, was obtained through extraction and ethanol precipitation. By employing methylation, GC–MS, FT-IR, and NMR analysis, GLP90-2 was identified as an arabinan having a molecular weight of 7.76 × 103 g/mol and consisting of three types of residues: α - l -Ara f- (1→, →5)- α - l -Ara f- (1→, and →3,5)- α - l -Ara f- (1→. The subsequent functional analysis revealed that GLP90-2 suppressed tumor development and metastasis in a zebrafish model. Mechanistic studies have shown that GLP90-2 promoted the maturation of DC2.4 cells and macrophages and enhanced the expression of immune-related cytokines, which may be attributed to the interaction between GLP90-2 and TLR-4. Additionally, GLP90-2 exhibited a strong interaction with PD-1, contributing to the activation of immunity. Furthermore, GLP90-2 suppressed angiogenesis in the transgenic zebrafish model, and this impact may be ascribed to the modulation of the VEGF/VEGFR-2 signaling pathway. All the results indicate that GLP90-2 demonstrates a strong tumor immunotherapy effect in vivo and has high potential for development. [Display omitted] • An arabinan (GLP90-2) was purified from the roots of Glehnia littoralis. • The structural property of GLP90-2 was characterized. • GLP90-2 showed good antitumor effects by activating the immune system. • GLP90-2 showed interaction with the proteins TLR-4, PD-1, and VEGF. • The antitumor activity was related to angiogenesis inhibition based on zebrafish models. [ABSTRACT FROM AUTHOR]

Epigenomic imbalance drives abnormal transcriptional processes, promoting the onset and progression of cancer. Although defective gene regulation generally affects carcinogenesis and tumor suppression networks, tumor immunogenicity and immune cells involved in antitumor responses may also be affected by epigenomic changes, which may have significant implications for the development and application of epigenetic therapy, cancer immunotherapy, and their combinations. Herein, we focus on the impact of epigenetic regulation on tumor immune cell function and the role of key abnormal epigenetic processes, DNA methylation, histone post-translational modification, and chromatin structure in tumor immunogenicity, and introduce these epigenetic research methods. We emphasize the value of small-molecule inhibitors of epigenetic modulators in enhancing antitumor immune responses and discuss the challenges of developing treatment plans that combine epigenetic therapy and immunotherapy through the complex interaction between cancer epigenetics and cancer immunology. In this review, we mainly review the effects of epigenetic modifications on chromosomal structure, thereby affecting gene expression and their functional realization. Combining cutting-edge epigenetic methods, we summarize in detail how DNA methylation, histone modification, and chromatin 3D structure affect the tumor microenvironment through immune cells to regulate tumorigenesis and tumor metastasis. At the same time, we summarize the effects of genomic topology on immune cells and tumors. This review provides detailed and in-depth methods and insights in epigenetics and tumor immunity, providing doctors and cancer patients with new ideas. [Display omitted] • This paper mainly studies the effect of Epigenetics regulation on tumor immune cell function. • The key abnormal Epigenetics processes include DNA methylation, histone modification and their influence in Chromatin structure to modulate tumor immune cells. • Summarized the research methods of these epigenetic modifications for the antitumor immunity. • The value of epigenetic modulators and small molecule inhibitors in enhancing anti-tumor immune response was emphasized. • The challenges of developing a combination of epigenetic and immunotherapy regimens were discussed. [ABSTRACT FROM AUTHOR]

Ferroptosis induced by RAS-selective lethal small molecule 3 (RSL3) can trigger anti-tumor immune responses by reversing the immunosuppressive tumor microenvironment (TME). However, it is challenging to achieve sufficient ferroptosis in the tumor via RSL3 alone. Because of the excellent reactive oxygen species (ROS) production capacity of glucose oxidase (GOx) and Fe3+, we hypothesized that GOx and Fe3+ could increase intracellular lipid peroxidation (LPO) accumulation, and strengthen RSL3-induced ferroptosis in tumor cells. Herein we designed an in-situ gelation strategy based on sodium alginate (SA) to realize localized transport and specific retention of GOx, RSL3, and Fe3+ in tumor tissues. We loaded hydrophobic RSL3 with the tannic acid (TA)/Fe3+ complexes to form nanoparticles (RTF NPs). GOx diluted in the SA solution was blended with RTF NPs to obtain a homogeneous solution. The solution could form hydrogels in the tumor site (RTFG@SA) upon injection. The retained GOx and Fe3+ amplified the induction of ferroptosis by RSL3, augmented immunogenic cell death (ICD) and promoted antitumor immunity. The RTFG@SA hydrogel presented a significant restraint of tumor growth and metastasis in the 4T1 tumor model. This hydrogel could offer an effective means of co-delivery of hydrophilic drugs, hydrophobic drugs, and metal ions. [Display omitted] [ABSTRACT FROM AUTHOR]

Abstract Background Recombinant human calcineurin B subunit (rhCNB) has been shown to be an immune‐stimulatory protein promoting cytokine production and inducing phenotypic maturation of Dendritic cells (DCs). In vivo, it has good antitumor efficacy, and has potential as an antitumor drug. Exogenous rhCNB was found to be internalized into tumor cells via the Toll‐like receptor 4 (TLR4) complex, but it was not known whether its immuno‐modulatory and antitumor functions involved entry by this same route. Methods The production and secretion of the cytokines and chemokines in innate immune cells induced by rhCNB were determined by ELISA, and the expression of CD40, CD80, CD86, and MHCII was analyzed by FACs. Experimental Lewis lung cancer (LLC) model was prepared in C57 BL/6 wild‐type (WT) mice, TLR4−/− mice or their littermates by the inoculation of LLCs in their right armpit, and then administrated daily intraperitoneal injections (0.2 mL) of normal saline, rhCNB 20 mg/kg, and rhCNB 40 mg/kg, respectively. Results Recombinant human calcineurin B subunit promoted the production of antitumor cytokines by innate immune cells, and culture supernatants of rhCNB‐stimulated immune cells induced apoptosis of LLCs. In addition, rhCNB up‐regulated CD40, CD80, CD86, and MHCII expression in macrophages and DCs in TLR4+ cells but failed to do so in TLR4 deficient cells. rhCNB also induced the formation of CD4+ and CD8+T cells in splenocytes from WT mice, but not from TLR4‐deficient littermates. Intraperitoneal administration of WT C57BL/6 mice with rhCNB resulted in a 50% reduction in LLC tumor growth, but failed to inhibit tumor growth in TLR4−/− littermates. Conclusions The in vivo antitumor and immunomodulatory effects of rhCNB are mediated by the TLR4. This conclusion is important for the further understanding and development of rhCNB as an antitumor drug.

Yuan Liu,1,2,* Jing-Jing Zhao,1,2,* Zi-Qi Zhou,1,2 Qiu-Zhong Pan,1,2 Qian Zhu,1,2 Yan Tang,1,2 Jian-Chuan Xia,1,2 De-Sheng Weng1,21State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China; 2Department of Biotherapy, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China*These authors contributed equally to this workIntroduction: IL-37 is a cytokine of IL-1 family that plays an important role in innate immunity and inflammation, and has been studied as a tumor suppressor in many cancers. However, it remains unclear whether IL-37 plays a regulatory role in tumor-infiltrating dendritic cells (DCs) in hepatocellular carcinoma (HCC).Materials and methods: We evaluated the relationship between IL-37 expression and tumor infiltration by DCs in 155 HCC samples through immunohistochemical analysis and Kaplan–Meier survival analysis. The effects of IL-37 on the anti-tumor activity of DCs were investigated by ELISA, flow cytometry, real-time quantitative PCR, cytotoxicity assays and tumorigenicity assays.Results: The expression level of IL-37 in HCC samples was positively correlated with the degree of CD1a+ DCs infiltration. The survival rates of patients with both a high expression of IL-37 and a high infiltration by CD1a+ DCs were significantly higher than those of patients with a low expression of IL-37 and a low infiltration by CD1a+ DCs. In vitro chemotaxis analysis indicated that HCC cells overexpressing IL-37 recruited more DCs by secreting higher levels of specific chemokines (eg, CCL3 and CCL20). In addition, IL-37 indirectly up-regulated the expression of major histocompatibility class II molecules, CD86 and CD40 on DCs by acting on tumor cells; IL-37 also indirectly enhanced the anti-tumor effect of T lymphocytes by stimulating DCs to secrete cytokines such as IL-2, IL-12, IL-12p70, interferon-α (IFN-α) and IFN-γ. Finally, overexpression IL-37 in HCC cells significantly delayed tumor growth and increased recruitment of CD11c+ DCs to tumor tissues was also revealed in vivo mouse model.Conclusion: DCs play an important role in IL-37 mediated anti-tumor immune responses in HCC, which may contribute to the development of novel cancer immunotherapeutic strategies.Keywords: IL-37, dendritic cells, antitumor immunity, hepatocellular carcinoma

A review article is an aftermath of the 11th International Congress on Autoimmunity and First Academy of Autoimmunity, happened 14th to 20th May, 2018 in Lisbon. The first part of paper discusses the formation, main problems and prospects for the development of Autoimmunology as a new integral branch of fundamental and clinical Medicine engaged in the research, diagnosis, treatment and prevention of autoimmune diseases of various organs and systems, totally circa 90 of them. A summary of all lectures conducted during the Academy of Autoimmunity is given, including a discussion of the newest and controversial aspects of the development of the modern concepts of the immune system, autoimmunity and autoimmune pathology. Article reviews data on the current problems of Immunology associated with the use of large databases of clinical and laboratory findings and extrapolation of animal experimentation data to humans. The newest ideas about congenital immunity, including the populations of innate lymphoid cells, on the role of various groups of receptors of the innate immunity system, on the participation of the mechanisms of innate immunity in pathogenesis of autoimmune disorders are highlighted. Modern concepts of antigen presentation are offered, including classification of dendritic cells, alternative pathways of macrophage activation, as well as on costimulatory and inhibitory interactions of ligands and receptors of lymphocytes and antigen-presenting cells. The latest data about the subpopulations of T lymphocytes and their role, including the functions of Tfh cells and the relationships of these subpopulations with various immune responses are highlighted. Influence of microbiota on T cell subpopulations is discussed. The main regularities of the phenomenon of immunological memory are formulated. The questions of antibody production and B lymphocyte functions are considered taking into account recently discovered mechanisms of intracellular penetration of immunoglobulins and details of affinity maturation of lymphoid clones. The new therapeutic approaches in the treatment of autoimmune diseases associated with influences on B and T lymphocytes are described. Mechanisms of central and peripheral autotolerance have been highlighted, taking into account data on the function of the AIRE gene and T regulators. The role of T regulators in placentation is considered. The role of interleukin-2 and its recombinant analogues in immune interactions is interpreted in a new way, taking into account not only their immunostimulating, but, under certain conditions, immunosuppressive potential also. Considerable attention has been paid to the inhibitory receptors of T lymphocytes and to immuno-biotherapeutic effects on them. The history and current status of Oncoimmunology and the use of blockers of inhibitory T lymphocyte receptors in Oncology, including the side effects of treatment with check-point inhibitors, are briefly discussed. Information was given on the held on 21-23 September 2018 2nd Academy of Autoimmunity in St. Petersburg.

Radiofrequency ablation (RFA) is a mini-invasive loco-regional ablation technique that is increasingly being used as a palliative treatment for pancreatic cancer and cholangiocarcinoma. Ablation-triggered immune system stimulation has been proposed as a mechanism behind the systemic effects of RFA. The aim of our study was to investigate the immune response to endoluminal biliary RFA. Peripheral blood samples were collected from patients with pancreatic cancer and cholangiocarcinoma randomised to receive endoluminal biliary radiofrequency ablation + stent (19 patients) or stent only (21 patients). We observed an early increase in IL-6 levels and a delayed increase in CXCL1, CXCL5, and CXCL11 levels as well as an increase in CD8+ and NK cells. However, these changes were not specific to RFA treatment. Explicitly in response to RFA, we observed a delayed increase in serum CXCL1 levels and an early decrease in the number of anti-inflammatory CD206+ blood monocytes. Our study provides the first evidence of endoluminal biliary RFA-based regulation of the systemic immune response in patients with pancreatic cancer and cholangiocarcinoma. These changes were characterised by a general inflammatory response. RFA-specific activation of the adaptive immune system was not confirmed.

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.

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.

The growing insights in the complex interactions between metastatic cancer-cells and platelets have revealed that platelet tumor cell interactions in the blood stream are an important factor supporting tumor metastasis. An increased coagulability of platelets facilitates the vascular evasion and establishment of solid tumor metastasis. Furthermore, platelets can support an immunosuppressive tumor microenvironment or shield tumor cells directly from engagement of cytotoxic lymphocytes as e.g., natural killer (NK) cells. Platelets are both in the tumor microenvironment and systemically the quantitatively most important source of TGF-β, which is a key cytokine for immunosuppression in the tumor microenvironment. If similar platelet-tumor interactions are of physiological relevance in hematological malignancies remains less well-studied. This might be important, as T- and NK cell mediated graft vs. leukemia effects (GvL) are well-documented and malignant hematological cells have a high exposure to platelets compared to solid tumors. As NK cell-based immunotherapies gain increasing attention as a therapeutic option for patients suffering from hematological and other malignancies, we review the known interactions between platelets and NK cells in the solid tumor setting and discuss how these could also apply to hematological cancers. We furthermore explore the possible implications for NK cell therapy in patients with solid tumors and patients who depend on frequent platelet transfusions. As platelets have a protective and supportive effect on cancer cells, the impact of platelet transfusion on immunotherapy and the combination of immunotherapy with platelet inhibitors needs to be evaluated.

In cutaneous T-cell lymphoma (CTCL), which arises from skin-tropic memory T cells, malignant T cells and benign T cells are confined in the same skin lesions. It is thus difficult to evaluate the phenotypic characteristics and functional activities of benign T cells in CTCL. Disialoganglioside with three glycosyl groups (GD3) is increasingly expressed on the surface of solid malignant tumor cells and takes part in tumor progression and suppression of tumor immunity. However, the role of GD3 in CTCL is not well-understood. In this study, the malignant and benign T cells in CTCL skin lesions were distinguished by flow cytometry and their phenotypic characteristics were compared with those of T cells from control skin specimens. In CTCL skin lesions, the benign T cells included limited resident memory T cells (TRM), which are sessile in skin and known to exert strong antitumor function. The benign T cells showed diminished Th17 property, and the expression of GD3 was high in the malignant T cells. The expression of GD3 in the malignant T cells inversely correlated with IL-17A production from the benign CD4 T cells. GD3 from the malignant T cells was implied to be involved in suppressing the Th17 activity of the benign T cells independent of the regulation of TRM differentiation in CTCL. Revealing the role of GD3 in inhibiting the production of IL-17A in CTCL would aid the understanding of the suppressive mechanism of the antitumor activity by malignant tumor cells.

Necroptosis is a form of programmed cell death (PCD) characterized by RIP3 mediated MLKL activation and increased membrane permeability via MLKL oligomerization. Tumor cell immunogenic cell death (ICD) has been considered to be essential for the anti-tumor response, which is associated with DC recruitment, activation, and maturation. In this study, we found that P. aeruginosa showed its potential to suppress tumor growth and enable long-lasting anti-tumor immunity in vivo. What’s more, phosphorylation- RIP3 and MLKL activation induced by P. aeruginosa infection resulted in tumor cell necrotic cell death and HMGB1 production, indicating that P. aeruginosa can cause immunogenic cell death. The necrotic cell death can further drive a robust anti-tumor response via promoting tumor cell death, inhibiting tumor cell proliferation, and modulating systemic immune responses and local immune microenvironment in tumor. Moreover, dying tumor cells killed by P. aeruginosa can catalyze DC maturation, which enhanced the antigen-presenting ability of DC cells. These findings demonstrate that P. aeruginosa can induce immunogenic cell death and trigger a robust long-lasting anti-tumor response along with reshaping tumor microenvironment.

Pyroptosis, a lytic pro-inflammatory type of programmed cell death, has been widely studied in diverse inflammatory disease models. Membrane perforation and cell swelling induced by cleaved gasdermin family members is the main characteristic of pyroptosis. Emerging evidence has revealed a complicated relationship between pyroptosis and cancer. On the one hand, as inflammatory cell death, pyroptosis provides a comfortable environment for tumor proliferation. On the other hand, excessive activation of pyroptosis can inhibit the development of tumor cells. In this review, we first summarized the latest progress about the molecular mechanism of pyroptosis. Then, members from gasdermin family, the central molecules of pyroptosis which formed pores on the cell membrane, were highlighted. In the second part of this review, we summarized drugs that induced pyroptosis in different tumors and their concrete mechanisms based on recent literature reports. In the final section, we discussed several hotspots in pyroptosis and cancer therapy, which will point out the direction of sequent research. In brief, inducing pyroptosis in cancer cells is a promising strategy for cancer therapy.

Ablative treatment evokes antitumor immunity, but knowledge on the emerging irreversible electroporation (IRE)-induced immunity in hepatocellular carcinoma (HCC) is limited. To investigate the immune effects induced by IRE and its role in preventing post-ablation HCC progression, a C57BL/6J mouse model bearing subcutaneous H22 hepatoma was employed. IRE treatment significantly suppresses HCC growth, and treated mice are tumor-free after secondary tumor injection and show increased splenic interferon-gamma (IFN-γ)+CD8+ T cells. Additionally, more CD8+ T and dendritic cells, but not CD4+ T, B or NK cells, infiltrate into peri-ablation zones after IRE at day 7. Depletion of CD8+ T cells induces local tumor regrowth and distant metastasis after IRE. Vaccination using IRE-processed H22 lysates prevents tumorigenesis in mice, suggesting a protective immune response. IRE also alleviates immunosuppression by reducing local and splenic Treg and PD-1+ T cells. Regarding mechanism, IRE induces cell necrosis and significant release of danger-associated molecular patterns including ATP, high mobility group box 1 and calreticulin that are pivotal to CD8+ T cell immunity. Together, IRE is a promising approach to evoke CD8+ T cell immunity, which help prevent post-ablation HCC progression. [ABSTRACT FROM AUTHOR]

In cutaneous T-cell lymphoma (CTCL), which arises from skin-tropic memory T cells, malignant T cells and benign T cells are confined in the same skin lesions. It is thus difficult to evaluate the phenotypic characteristics and functional activities of benign T cells in CTCL. Disialoganglioside with three glycosyl groups (GD3) is increasingly expressed on the surface of solid malignant tumor cells and takes part in tumor progression and suppression of tumor immunity. However, the role of GD3 in CTCL is not well-understood. In this study, the malignant and benign T cells in CTCL skin lesions were distinguished by flow cytometry and their phenotypic characteristics were compared with those of T cells from control skin specimens. In CTCL skin lesions, the benign T cells included limited resident memory T cells (TRM), which are sessile in skin and known to exert strong antitumor function. The benign T cells showed diminished Th17 property, and the expression of GD3 was high in the malignant T cells. The expression of GD3 in the malignant T cells inversely correlated with IL-17A production from the benign CD4 T cells. GD3 from the malignant T cells was implied to be involved in suppressing the Th17 activity of the benign T cells independent of the regulation of TRM differentiation in CTCL. Revealing the role of GD3 in inhibiting the production of IL-17A in CTCL would aid the understanding of the suppressive mechanism of the antitumor activity by malignant tumor cells. [ABSTRACT FROM AUTHOR]

The growing insights in the complex interactions between metastatic cancer-cells and platelets have revealed that platelet tumor cell interactions in the blood stream are an important factor supporting tumor metastasis. An increased coagulability of platelets facilitates the vascular evasion and establishment of solid tumor metastasis. Furthermore, platelets can support an immunosuppressive tumor microenvironment or shield tumor cells directly from engagement of cytotoxic lymphocytes as e.g., natural killer (NK) cells. Platelets are both in the tumor microenvironment and systemically the quantitatively most important source of TGF-β, which is a key cytokine for immunosuppression in the tumor microenvironment. If similar platelet-tumor interactions are of physiological relevance in hematological malignancies remains less well-studied. This might be important, as T- and NK cell mediated graft vs. leukemia effects (GvL) are well-documented and malignant hematological cells have a high exposure to platelets compared to solid tumors. As NK cell-based immunotherapies gain increasing attention as a therapeutic option for patients suffering from hematological and other malignancies, we review the known interactions between platelets and NK cells in the solid tumor setting and discuss how these could also apply to hematological cancers. We furthermore explore the possible implications for NK cell therapy in patients with solid tumors and patients who depend on frequent platelet transfusions. As platelets have a protective and supportive effect on cancer cells, the impact of platelet transfusion on immunotherapy and the combination of immunotherapy with platelet inhibitors needs to be evaluated. [ABSTRACT FROM AUTHOR]

Suppressive mechanisms operating within T cells are linked to immune dysfunction in the tumor microenvironment. We have previously reported using adoptive T cell immunotherapy models that tumor–bearing mice treated with a regimen of proteasome inhibitor, bortezomib - a dipeptidyl boronate, show increased antitumor lymphocyte effector function and survival. Here, we identify a mechanism for the improved antitumor CD8+ T cell function following bortezomib treatment. Intravenous administration of bortezomib at a low dose (1 mg/kg body weight) in wild-type or tumor-bearing mice altered the expression of a number of miRNAs in CD8+ T cells. Specifically, the effect of bortezomib was prominent on miR-155 - a key cellular miRNA involved in T cell function. Importantly, bortezomib–induced upregulation of miR-155 was associated with the downregulation of its targets, the suppressor of cytokine signaling 1 (SOCS1) and inositol polyphosphate-5-phosphatase (SHIP1). Genetic and biochemical analysis confirmed a functional link between miR-155 and these targets. Moreover, activated CD8+ T cells treated with bortezomib exhibited a significant reduction in programmed cell death-1 (PD-1) expressing SHIP1+ phenotype. These data underscore a mechanism of action by which bortezomib induces miR-155–dependent downregulation of SOCS1 and SHIP1 negative regulatory proteins, leading to a suppressed PD-1–mediated T cell exhaustion. Collectively, data provide novel molecular insights into bortezomib–mediated lymphocyte–stimulatory effects that could overcome immunosuppressive actions of tumor on antitumor T cell functions. The findings support the approach that bortezomib combined with other immunotherapies would lead to improved therapeutic outcomes by overcoming T cell exhaustion in the tumor microenvironment. [ABSTRACT FROM AUTHOR]

Pyroptosis, a lytic pro-inflammatory type of programmed cell death, has been widely studied in diverse inflammatory disease models. Membrane perforation and cell swelling induced by cleaved gasdermin family members is the main characteristic of pyroptosis. Emerging evidence has revealed a complicated relationship between pyroptosis and cancer. On the one hand, as inflammatory cell death, pyroptosis provides a comfortable environment for tumor proliferation. On the other hand, excessive activation of pyroptosis can inhibit the development of tumor cells. In this review, we first summarized the latest progress about the molecular mechanism of pyroptosis. Then, members from gasdermin family, the central molecules of pyroptosis which formed pores on the cell membrane, were highlighted. In the second part of this review, we summarized drugs that induced pyroptosis in different tumors and their concrete mechanisms based on recent literature reports. In the final section, we discussed several hotspots in pyroptosis and cancer therapy, which will point out the direction of sequent research. In brief, inducing pyroptosis in cancer cells is a promising strategy for cancer therapy. [ABSTRACT FROM AUTHOR]

In hepatocellular carcinoma patients, due to the microenvironmental specificity of liver, the tumor microenvironment exhibits high immunosuppression and drug resistance, resulting in excessive or insufficient responses to immunotherapy. The dynamic interactions between tumor cells and immune modulators in the TME significantly impact the occurrence and development of tumors, efficacy, and drug resistance, which can create a much more positive response to immunotherapy. Moreover, with the wide application of single-cell sequencing technology in the TME, increasing evidence shows an interaction network among cells. Sequencing results suggest that specific tumor-associated macrophages are a hub node, connecting different cell populations in the cell interaction network, and can could regulate tumor generation and antitumor immunity. This review focused on therapeutic targets that could be targeted to remodel the tumor microenvironment and reprogram the tumor-associated macrophage phenotype in hepatocellular carcinoma patients, thereby improving immunotherapeutic efficacy. [ABSTRACT FROM AUTHOR]

Necroptosis is a form of programmed cell death (PCD) characterized by RIP3 mediated MLKL activation and increased membrane permeability via MLKL oligomerization. Tumor cell immunogenic cell death (ICD) has been considered to be essential for the anti-tumor response, which is associated with DC recruitment, activation, and maturation. In this study, we found that P. aeruginosa showed its potential to suppress tumor growth and enable long-lasting anti-tumor immunity in vivo. What's more, phosphorylation- RIP3 and MLKL activation induced by P. aeruginosa infection resulted in tumor cell necrotic cell death and HMGB1 production, indicating that P. aeruginosa can cause immunogenic cell death. The necrotic cell death can further drive a robust anti-tumor response via promoting tumor cell death, inhibiting tumor cell proliferation, and modulating systemic immune responses and local immune microenvironment in tumor. Moreover, dying tumor cells killed by P. aeruginosa can catalyze DC maturation, which enhanced the antigen-presenting ability of DC cells. These findings demonstrate that P. aeruginosa can induce immunogenic cell death and trigger a robust long-lasting anti-tumor response along with reshaping tumor microenvironment. [ABSTRACT FROM AUTHOR]

Although colorectal cancer is the leading cause of death in patients with liver metastases, there are no efficient treatments available. Oncolytic virus therapy, a new type of tumor therapy, has become a potential solution. With the goal of improving the treatment of advanced colorectal cancer, we applied oncolytic herpes simplex virus type 2 (oHSV2) in a mouse model of colorectal cancer with liver metastasis. Compared with the control, oHSV2 effectively inhibited the growth of subcutaneous primary tumors, significantly reduced the number and size of liver metastases, and prolonged the median survival time of the mice. In addition, neutrophils, natural killer (NK) cells, T cells, B cells, and cytokines in the tumor microenvironment and the body were all activated, and their frequencies increased significantly. Moreover, the proportion of immunosuppressive myeloid-derived suppressor cells decreased. oHSV2 treatment, which establishes an effective long-term antitumor immune response, is strongly resistant to rechallenge by the same tumor. Our data show that oHSV2 can effectively kill the primary tumor and attack distal and metastatic tumors by inducing immune responses, resulting in lasting antitumor efficacy and preventing tumor recurrence. It is believed that oHSV2 has good clinical application prospects. [ABSTRACT FROM AUTHOR]

Although PD-1/PD-L1 blockade therapy confers salutary effects across cancer types, their efficacy in Extranodal Natural killer/T-cell lymphoma (ENKTCL) patients is limited and unpredictable. Here, we comprehensively evaluated the expression profile of a panel of immune-regulatory makers to identify novel prognostic biomarkers and/or therapeutic targets for this malignancy. Using immunohistochemistry and multiplex immunofluorescence, we found that the expression of VISTA (88.1%) was predominantly in CD68+ macrophages and much higher than PD-L1 expression (68.7%) in ENKTCL. B7-H4 and HHLA2 proteins were not detected in ENKTCL. B7-H3 was expressed in minority of ENKTCL patients (13.7%) and mainly colocalized with CD31. A close correlation was detected between VISTA and PD-L1, but they were not co-expressed in the same cells. High expressions of VISTA or PD-L1 were significantly associated with detrimental clinicopathological characteristics, dismal prognosis, and high density of CD8+ TILs, and high VISTA expression was also significantly associated with high density of Foxp3+ TILs. VISTA combined with PD-L1 was an independent prognostic factor for PFS and OS. Moreover, the patients with high VISTA showed a poor response to PD-1 blockades in ENKTCL. In conclusion, these findings provide a rationale for VISTA as an ideal immunotherapeutic target next to PD-L1 for ENKTCL.

Formyl peptide receptor 1 (FPR1) plays a key regulatory role in innate and adaptive immunity. Recently, we reported that the CC genotype of FPR1-E346A (rs867228, c. 1037 A > C) is an independent biomarker for patients with locally advanced rectal cancer (LARC) who received preoperative concurrent chemoradiotherapy (CCRT). Pharmacologic inhibition of FPR1 decreased the migration and infiltration of T lymphocytes into tumor microenvironment after CCRT.

We report a new class of ruthenium (Ru)-based photosensitizers that induce potent cytotoxicity in melanoma cells following activation with NIR light. In addition to the direct cytotoxic effect, this Ru-based photodynamic therapy induces immunogenic cell death in melanoma cells that can be therapeutically exploited to establish protective antitumor immunity.

While chemotherapy and radiotherapy remain the first-line approaches for the management of most unresectable tumors, immunotherapy has emerged in the past two decades as a game-changing treatment, notably with the clinical success of immune checkpoint inhibitors. Immunotherapies aim at (re)activating anticancer immune responses which occur in two main steps: (1) the activation and expansion of tumor-specific T cells following cross-presentation of tumor antigens by specialized myeloid cells (priming phase); and (2) the immunological clearance of malignant cells by these antitumor T lymphocytes (effector phase). Therapeutic vaccines, adjuvants, monoclonal antibodies, cytokines, immunogenic cell death-inducing agents including oncolytic viruses, anthracycline-based chemotherapy and radiotherapy, as well as adoptive cell transfer, all act at different levels of this cascade to (re)instate cancer immunosurveillance. Intratumoral delivery of these immunotherapeutics is being tested in clinical trials to promote superior antitumor immune activity in the context of limited systemic toxicity.

The tumor microenvironment (TME) is complex, and its composition and dynamics determine tumor fate. From tumor cells themselves, with their capacity for unlimited replication, migration, and invasion, to fibroblasts, endothelial cells, and immune cells, which can have pro and/or anti-tumor potential, interaction among these elements determines tumor progression. The understanding of molecular pathways involved in immune escape has permitted the development of cancer immunotherapies. Targeting molecules or biological processes that inhibit antitumor immune responses has allowed a significant improvement in cancer patient’s prognosis. Autophagy is a cellular process required to eliminate dysfunctional proteins and organelles, maintaining cellular homeostasis. Usually a process associated with protection against cancer, autophagy associated to cancer cells has been reported in response to hypoxia, nutrient deficiency, and oxidative stress, conditions frequently observed in the TME. Recent studies have shown a paradoxical association between autophagy and tumor immune responses. Tumor cell autophagy increases the expression of inhibitory molecules, such as PD-1 and CTLA-4, which block antitumor cytotoxic responses. Moreover, it can also directly affect antitumor immune responses by, for example, degrading NK cell-derived granzyme B and protecting tumor cells. Interestingly, the activation of autophagy on dendritic cells has the opposite effects, enhancing antigen presentation, triggering CD8+ T cells cytotoxic activity, and reducing tumor growth. Therefore, this review will focus on the most recent aspects of autophagy and tumor immune environment. We describe the dual role of autophagy in modulating tumor immune responses and discuss some aspects that must be considered to improve cancer treatment.

Along with the clinical success of immuno-oncology drugs and cellular therapies, T-cell biology has attracted considerable attention in the immunology community. Long-term immunity, traditionally analyzed in the context of infection, is increasingly studied in cancer. Many signaling pathways, transcription factors, and metabolic regulators have been shown to participate in the formation of memory T cells. There is increasing evidence that the signal transducer and activator of transcription-3 (STAT3) signaling pathway is crucial for the formation of long-term T-cell immunity capable of efficient recall responses. In this review, we summarize what is currently known about STAT3 role in the context of memory T-cell formation and antitumor immunity.

Immunotherapy using chimeric antigen receptor (CAR) T cells is a rapidly emerging modality that engineers T cells to redirect tumor-specific cytotoxicity. CAR T cells have been well characterized for their efficacy against B cell malignancies, and rigorously studied in other types of tumors. Preclinical evaluation of CAR T cell function, including direct tumor killing, cytokine production, and memory responses, is crucial to the development and optimization of CAR T cell therapies. Such comprehensive examinations are usually performed in different types of models. Model establishment should focus on key challenges in the clinical setting and the capability to generate reliable data to indicate CAR T cell therapeutic potency in the clinic. Further, modeling the interaction between CAR T cells and tumor microenvironment provides additional insight for the future endeavors to enhance efficacy, especially against solid tumors. This review will summarize both in vitro and in vivo models for CAR T cell functional evaluation, including how they have evolved with the needs of CAR T cell research, the information they can provide for preclinical assessment of CAR T cell products, and recent technology advances to test CAR T cells in more clinically relevant models.

While chemotherapy and radiotherapy remain the first-line approaches for the management of most unresectable tumors, immunotherapy has emerged in the past two decades as a game-changing treatment, notably with the clinical success of immune checkpoint inhibitors. Immunotherapies aim at (re) activating anticancer immune responses which occur in two main steps: (1) the activation and expansion of tumor-specific T cells following cross-presentation of tumor antigens by specialized myeloid cells (priming phase); and (2) the immunological clearance of malignant cells by these antitumor T lymphocytes (effector phase). Therapeutic vaccines, adjuvants, monoclonal antibodies, cytokines, immunogenic cell death-inducing agents including oncolytic viruses, anthracycline-based chemotherapy and radio-therapy, as well as adoptive cell transfer, all act at different levels of this cascade to (re)instate cancer immunosurveillance. Intratumoral delivery of these immunotherapeutics is being tested in clinical trials to promote superior antitumor immune activity in the context of limited systemic toxicity. [ABSTRACT FROM AUTHOR]

The utilization of biologically produced cells to treat diseases is a revolutionary invention in modern medicine after chemically synthesized small molecule drugs and biochemically made protein drugs. Cells are basic units of life with diverse functions in mature and developing organs, which biological properties could be utilized as a promising therapeutic approach for currently intractable and incurable diseases. Xenogeneic cell therapy utilizing animal cells other than human for medicinal purpose has been studied as a new way of treating diseases. Xenogeneic cell therapy is considered as a potential regenerative approach to fulfill current unmet medical needs because xenogeneic cells could be isolated from different animal organs and expanded ex vivo as well as maintain the characteristics of original organs, providing a versatile and plenty cell source for cell-based therapeutics beside autologous and allogeneic sources. The swine species is considered the most suitable source because of the similarity with humans in size and physiology of many organs in addition to the economic and ethical reasons plus the possibility of genetic modification. This review discusses the old proposed uses of xenogeneic cells such as xenogeneic pancreatic islet cells, hepatocytes and neuronal cells as a living drug for the treatment of degenerative and organ failure diseases. Novel applications of xenogeneic mesenchymal stroma cells and urothelial cells are also discussed. There are formidable immunological barriers toward successful cellular xenotransplantation in clinic despite major progress in the development of novel immunosuppression regimens and genetically multimodified donor pigs. However, immunological barriers could be turn into immune boosters by using xenogeneic cells of specific tissue types as a novel immunotherapeutic agent to elicit bystander antitumor immunity due to rejection immune responses. Xenogeneic cells have the potential to become a safe and efficacious option for intractable diseases and hard-to-treat cancers, adding a new class of cellular medicine in our drug armamentarium. [ABSTRACT FROM AUTHOR]

Pyroptosis is a well-documented form of programmed cell death caused by the gasdermin-driven perforation of cell membranes. Selective induction of pyroptosis in tumor cells represents a promising antitumor strategy to enhance the efficacy of immunotherapy. In this study, we established a recombinant protein-based immunopyroptotin strategy that led to the intratumoral induction of pyroptosis for HER2-directed therapy. Long-lasting immunopyroptotins were constructed by sequentially fusing the humanized anti-HER2 single-chain antibody P1h3, albumin-binding peptide (ABD035 or dAb7h8), cathepsin B-cleavable peptide B2, endosome-disruptive peptide E5C3, and active pyroptotic effector gasdermin D-N fragment (GN). After purification, we evaluated the cytotoxicity and antitumor immune responses primarily induced by the immunopyroptotins in HER2-overexpressing breast cancer cells. The resulting ABD035-immunoGN and dAb7h8-immunoGN showed improved in vitro cytotoxicity in HER2-overexpressing cancer cells compared with that in the immunotBid that we previously generated to induce tumor cell apoptosis. The binding of long-lasting immunopyroptotins to albumin increased the half-life by approximately 7-fold in nude mice. The enhanced antitumor efficacy of long-lasting immunopyroptotins was confirmed in both N87 tumor-bearing T cell-deficient mice and 4T1-hHER2 bilateral tumor-bearing immunocompetent mice. Immunopyroptotin treatment elicited systemic antitumor immune responses involving CD8 + T cells and mature dendritic cells and upregulated the expression of proinflammatory cytokines, leading to sustained remission of non-injected distant tumors. This study extends the repertoire of antibody-based therapeutics through the tumor-targeted delivery of a constitutively active pore-forming gasdermin-N fragment, which shows great potential for pyroptosis-based antitumor therapy., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Jing Zhao reports financial support was provided by 10.13039/501100001809National Natural Science Foundation of China. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)