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Simple Summary: This study investigates the impact of the BRAFV600E mutation, present in half of melanoma cases, on immune microenvironment and therapeutic response. Analyzing the Cancer Genome Atlas data, we uncover that the mutation correlates with reduced tumor mutation burden, indicating a lower generation of immune-stimulating neopeptides. Examination of immune subtypes reveal heightened immunosuppression in BRAFV600E-mutated tumors. Using melanoma cell lines harboring different genomic profiles, we observed an enhanced response to immunogenic cell death (ICD)—a crucial process eliciting anti-tumor immune responses—mediated by photodynamic therapy (PDT). Transcriptomic analysis highlights upregulation of IFNAR1, IFNAR2, and CXCL10 genes in BRAFV600E-mutated cells, suggesting their role in ICD. Our results describe the intricate relationship between the BRAFV600E mutation and immune responses, hinting at a potential link between this mutation and responsiveness to ICD-inducing therapies, particularly PDT, putatively linked to increased IFN-1 pathway activation. The BRAFV600E mutation, found in approximately 50% of melanoma cases, plays a crucial role in the activation of the MAPK/ERK signaling pathway, which promotes tumor cell proliferation. This study aimed to evaluate its impact on the melanoma immune microenvironment and therapeutic responses, particularly focusing on immunogenic cell death (ICD), a pivotal cytotoxic process triggering anti-tumor immune responses. Through comprehensive in silico analysis of the Cancer Genome Atlas data, we explored the association between the BRAFV600E mutation, immune subtype dynamics, and tumor mutation burden (TMB). Our findings revealed that the mutation correlated with a lower TMB, indicating a reduced generation of immunogenic neoantigens. Investigation into immune subtypes reveals an exacerbation of immunosuppression mechanisms in BRAFV600E-mutated tumors. To assess the response to ICD inducers, including doxorubicin and Me-ALA-based photodynamic therapy (PDT), compared to the non-ICD inducer cisplatin, we used distinct melanoma cell lines with wild-type BRAF (SK-MEL-2) and BRAFV600E mutation (SK-MEL-28, A375). We demonstrated a differential response to PDT between the WT and BRAFV600E cell lines. Further transcriptomic analysis revealed upregulation of IFNAR1, IFNAR2, and CXCL10 genes associated with the BRAFV600E mutation, suggesting their involvement in ICD. Using a gene reporter assay, we showed that PDT robustly activated the IFN-1 pathway through cGAS-STING signaling. Collectively, our results underscore the complex interplay between the BRAFV600E mutation and immune responses, suggesting a putative correlation between tumors carrying the mutation and their responsiveness to therapies inducing the IFN-1 pathway, such as the ICD inducer PDT, possibly mediated by the elevated expression of IFNAR1/2 receptors [ABSTRACT FROM AUTHOR]

Simple Summary: Since TIM-3 on T cells or dendritic cells (DCs) has recently emerged as an attractive target for immunotherapy, we examined its expression on DCs using transcriptomic data from a public database and immunohistochemical evaluations from our cohorts of colorectal cancer. The expression of HAVCR2 (TIM-3) was strongly associated with the infiltration of DCs within the tumor microenvironment, and immunohistochemical staining of clinical tissue samples revealed that tumor-infiltrating DCs expressed TIM-3; however, their number at the tumor-invasive front significantly decreased with stage progression. Among vitro-generated DCs, TIM-3 expression was higher on immature DCs than on mature DCs, while Western blotting showed that STING expression was higher on mature DCs than on immature DCs. TIM-3 was originally identified as a negative regulator of helper T cells and is expressed on dendritic cells (DCs). Since the inhibition of TIM-3 on DCs has been suggested to enhance T cell-mediated anti-tumor immunity, we examined its expression on DCs within the tumor microenvironment (TME) in colorectal cancer (CRC) using transcriptomic data from a public database (n = 592) and immunohistochemical evaluations from our cohorts of CRC (n = 115). The expression of TIM-3 on DCs in vitro was examined by flow cytometry, while the expression of its related molecules, cGAS and STING, on immature and mature DCs was assessed by Western blotting. The expression of HAVCR2 (TIM-3) was strongly associated with the infiltration of DCs within the TME of CRC. Immunohistochemical staining of clinical tissue samples revealed that tumor-infiltrating DCs expressed TIM-3; however, their number at the tumor-invasive front significantly decreased with stage progression. TIM-3 expression was higher on immature DCs than on mature DCs from several different donors (n = 6). Western blot analyses showed that the expression of STING was higher on mature DCs than on immature DCs, which was opposite to that of TIM-3. We demonstrated that TIM-3 was highly expressed on tumor-infiltrating DCs of CRC and that its expression was higher on immature DCs than on mature DCs. [ABSTRACT FROM AUTHOR]

Simple Summary: The cGAS-STING cellular signaling pathway is a key member of the DNA damage response, whose role is to repair the DNA damage that occurs naturally during the life of a cell. Interestingly, cGAS-STING is known to promote immune responses against tumors, and is being explored for its potential use in cancer immunotherapy applications. The DNA damage caused by traditional cancer treatments such as radiation and chemotherapy is one of the main ways in which cancer cells are eradicated, and is increasingly being linked with cGAS-STING activation. In this review, we summarize the many reports of cGAS-STING activation by different conventional cancer therapies, highlighting the roles of their targets in the DNA damage response. As part of the review, we discuss an emerging "chemoimmunotherapy" concept where the DNA-damaging activity of these conventional therapies can potentially be exploited for its beneficial stimulation of anticancer immune responses by way of cGAS-STING activation. The potential advantages of such an approach are highlighted, and it becomes clear that targeted nanoparticle delivery systems will be critical in minimizing the associated immunotoxic and inflammatory activities of the entrapped chemotherapeutics. Many traditional cancer treatments such as radiation and chemotherapy are known to induce cellular DNA damage as part of their cytotoxic activity. The cGAS-STING signaling axis, a key member of the DNA damage response that acts as a sensor of foreign or aberrant cytosolic DNA, is helping to rationalize the DNA-damaging activity of these treatments and their emerging immunostimulatory capacity. Moreover, cGAS-STING, which is attracting considerable attention for its ability to promote antitumor immune responses, may fundamentally be able to address many of the barriers limiting the success of cancer immunotherapy strategies, including the immunosuppressive tumor microenvironment. Herein, we review the traditional cancer therapies that have been linked with cGAS-STING activation, highlighting their targets with respect to their role and function in the DNA damage response. As part of the review, an emerging "chemoimmunotherapy" concept whereby DNA-damaging agents are used for the indirect activation of STING is discussed as an alternative to the direct molecular agonism strategies that are in development, but have yet to achieve clinical approval. The potential of this approach to address some of the inherent and emerging limitations of cGAS-STING signaling in cancer immunotherapy is also discussed. Ultimately, it is becoming clear that in order to successfully employ the immunotherapeutic potential of the cGAS-STING axis, a balance between its contrasting antitumor and protumor/inflammatory activities will need to be achieved. [ABSTRACT FROM AUTHOR]

Simple Summary: As the incidence and survival of patients with brain metastases improve, the burden of treatment-related neurotoxicities will increase for patients and healthcare systems. Radiation necrosis, or injury and inflammation to normal brain tissue, is an increasingly common and deleterious adverse effect of radiation therapy that can contribute to patient morbidity and mortality. We aimed to characterize the biological mechanisms that drive necrosis and the risks associated with multimodal therapy, including immunotherapy. This review additionally provides management guidelines and an overview of novel opportunities for investigation. Awareness of the presentation, risk factors, biological mechanisms, and management options for necrosis are crucial for optimal patient-centered care and discovery. Radiation necrosis, also known as treatment-induced necrosis, has emerged as an important adverse effect following stereotactic radiotherapy (SRS) for brain metastases. The improved survival of patients with brain metastases and increased use of combined systemic therapy and SRS have contributed to a growing incidence of necrosis. The cyclic GMP-AMP (cGAMP) synthase (cGAS) and stimulator of interferon genes (STING) pathway (cGAS-STING) represents a key biological mechanism linking radiation-induced DNA damage to pro-inflammatory effects and innate immunity. By recognizing cytosolic double-stranded DNA, cGAS induces a signaling cascade that results in the upregulation of type 1 interferons and dendritic cell activation. This pathway could play a key role in the pathogenesis of necrosis and provides attractive targets for therapeutic development. Immunotherapy and other novel systemic agents may potentiate activation of cGAS-STING signaling following radiotherapy and increase necrosis risk. Advancements in dosimetric strategies, novel imaging modalities, artificial intelligence, and circulating biomarkers could improve the management of necrosis. This review provides new insights into the pathophysiology of necrosis and synthesizes our current understanding regarding the diagnosis, risk factors, and management options of necrosis while highlighting novel avenues for discovery. [ABSTRACT FROM AUTHOR]

Simple Summary: Isocitrate dehydrogenase 3α (IDH3α) is highly expressed in many cancers and is associated with poor patient prognosis. However, it is not clear whether the aberrant expression of IDH3α is related to the efficacy of chemoimmunotherapy against cancer. We used in vivo and in vitro experiments and bioinformatics to explore the potential role of IDH3α in chemoimmunotherapy treatment. Our results indicate that IDH3α overexpression leads to resistance to chemoimmunotherapy by regulating the acidic tumor microenvironments and the cGAS–STING pathway. Our results provide initial preclinical evidence that the combination of IDH3α knockdown and chemoimmunotherapy may improve the therapy for cancer patients. In recent years, chemoimmunotherapy has become effective in some advanced cancers, but its effect is still limited. Transcriptional upregulation of isocitrate dehydrogenase 3α (IDH3α) can promote tumor initiation and progression. However, it is not clear whether the aberrant expression of IDH3α is related to the efficacy of chemoimmunotherapy in cancers. Here, we found that IDH3α was elevated in uterine cervical cancer (UCC) and lung adenocarcinoma (LUAD) samples by using public databases. High expression of IDH3α could promote the epithelial–mesenchymal transition (EMT), alter the intracellular redox status, promote glycolysis, and induce an acidic microenvironments in cancer cells. Furthermore, we found that inhibition of IDH3α combined with chemoimmunotherapy (cisplatin and programmed cell death ligand 1 (PD-L1) antibodies) activated the cGAS–STING pathway, promoted CD8+ T cell infiltration, and decreased tumor growth in mouse models of cervical cancer. In conclusion, our data indicate that silencing IDH3α sensitizes tumors to chemoimmunotherapy by modulating the acidic microenvironment and activating the cGAS–STING pathway. [ABSTRACT FROM AUTHOR]

Simple Summary: Microtubule-targeting agents are a class of chemotherapeutics used to treat triple-negative breast cancer (TNBC). These include drugs such as eribulin that depolymerize microtubules, as well as microtubule stabilizing taxanes such as paclitaxel. TNBC is a relatively immunogenic form of breast cancer and one strategy to further increase immunogenicity is through activation of the cGAS-STING innate immune sensing pathway. We demonstrate that eribulin enhances interferon production in combination with STING agonists undergoing clinical development in immune and TNBC cells. This phenotype is shared with other microtubule destabilizers, but not with stabilizers, suggesting a mechanism downstream of microtubule depolymerization. We determined that eribulin also enhanced immunogenic responses in vivo and improved antitumor efficacy in a spontaneous murine mammary tumor model when combined with a STING agonist. These findings highlight important mechanistic distinctions between microtubule targeted chemotherapeutic drugs and provide an opportunity to improve the efficacy of immunotherapies using a compound currently used in TNBC. Eribulin is a microtubule destabilizer used in the treatment of triple-negative breast cancer (TNBC). Eribulin and other microtubule targeted drugs, such as the taxanes, have shared antimitotic effects, but differ in their mechanism of microtubule disruption, leading to diverse effects on cellular signaling and trafficking. Herein, we demonstrate that eribulin is unique from paclitaxel in its ability to enhance expression of the immunogenic cytokine interferon beta (IFNβ) in combination with STING agonists in both immune cells and TNBC models, including profound synergism with ADU-S100 and E7766, which are currently undergoing clinical trials. The mechanism by which eribulin enhances STING signaling is downstream of microtubule disruption and independent of the eribulin-dependent release of mitochondrial DNA. Eribulin did not override the requirement of ER exit for STING activation and did not inhibit subsequent STING degradation; however, eribulin significantly enhanced IRF3 phosphorylation and IFNβ production downstream of the RNA sensing pathway that converges on this transcription factor. Additionally, we found that eribulin enhanced the population of activated CD4+ T-cells in vivo when combined with either a STING agonist or tumor, demonstrating the ability to function as an immune adjuvant. We further interrogated the combination of eribulin with ADU-S100 in the MMTV-PyVT spontaneous murine mammary tumor model where we observed significant antitumor efficacy with combination treatment. Together, our findings demonstrate that microtubule targeted chemotherapeutics have distinct immunological effects and that eribulin's ability to enhance innate immune sensing pathways supports its use in combination with immunotherapies, such as STING agonists, for the more effective treatment of TNBC and other malignancies. [ABSTRACT FROM AUTHOR]