Journal for Immunotherapy of Cancer最新文献

{"title":"Enhanced antitumor immunity of VNP20009-CCL2-CXCL9 via the cGAS/STING axis in osteosarcoma lung metastasis.","authors":"Ruixuan Liu, Qi Liu, Yuming Wang, Tianyi Liu, Zhusheng Zhang, Chong Zhao, Haipeng Tao, Elizabeth Ogando-Rivas, Paul Castillo, Weibin Zhang","doi":"10.1136/jitc-2025-012269","DOIUrl":"https://doi.org/10.1136/jitc-2025-012269","url":null,"abstract":"<p><strong>Background: </strong>Osteosarcoma (OS) with pulmonary metastasis remains challenging due to limited treatment options and the immunosuppressive nature of the tumor microenvironment (TME). Bacteria-mediated cancer therapy has emerged as a promising strategy for solid tumors but often suffers from limited efficacy due to the immunosuppressive TME, which restricts the intensity and durability of the antitumor immune response. To overcome these challenges, we engineered a novel Salmonella strain, VNP20009-CCL2-CXCL9 (VNP-C-C), leveraging the intrinsic tumor tropism of <i>Salmonella typhimurium</i> VNP20009 (VNP) and improving immune modulation through the recruitment of effector immune cells into the TME by the chemokines CCL2 and CXCL9.</p><p><strong>Methods: </strong>VNP-C-C was genetically engineered through electroporation of Plac-CCL2-CXCL9 plasmid and validated in vitro. Its antitumor efficacy, immune regulation capacity and immunomodulatory mechanisms were evaluated in vitro by using OS cell lines and immune cells (dendritic cells (DCs) and macrophages (Mφs)) and in vivo by using both immunocompromised and immunocompetent mouse models of OS lung metastasis.</p><p><strong>Results: </strong>VNP-C-C effectively accumulated within tumors, triggering immunogenic cell death and subsequently activating the cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes (STING) pathway, thereby robustly promoting type I interferon secretion. The chemokines CCL2 and CXCL9 amplified the immune response by recruiting DCs, Mφs, and T cells to the TME. This orchestrated immune modulation reprogrammed tumor-associated macrophages to an antitumor phenotype, induced DCs maturation, significantly increased T-cell infiltration and activation within tumors, and promoted systemic T-cell memory formation in peripheral lymphoid organs. These effects collectively inhibited OS lung metastasis progression and provided survival benefits in mouse models.</p><p><strong>Conclusion: </strong>The engineered bacterial strain VNP-C-C effectively converts the OS lung metastatic TME into a pro-inflammatory milieu, thereby stimulating robust innate and adaptive immune responses. This offers a highly promising therapeutic avenue for OS lung metastasis with considerable translational potential in cancer immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 7","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Prior chemotherapy deteriorates T-cell quality for CAR T-cell therapy in B-cell non-Hodgkin's lymphoma.","authors":"","doi":"10.1136/jitc-2024-010709corr1","DOIUrl":"https://doi.org/10.1136/jitc-2024-010709corr1","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 7","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ADI-270: an armored allogeneic gamma delta T cell therapy designed to target CD70-expressing solid and hematologic malignancies.","authors":"Kevin P Nishimoto, Gauri Lamture, Yvan Chanthery, Alexander G Teague, Yogendra Verma, Melinda Au, Morgan Smith-Boeck, Michael Salum, Pranav Murthy, Smitha R Y Gundurao, Ramandeep Kaur, Jie Zhang, Aruna Azameera, Jonathan T S Wong, Elizabeth B Speltz, Katherine M Wang, Amy Doan, Jyothi Sethuraman, Dishant Bhatwala, Ana Giner-Rubio, Pavan Puligujja, Helen Budworth, Christopher J Rold, Swapna Panuganti, Aya Jakobovits, Marissa Herrman, Arun Bhat, Shon Green, Blake T Aftab","doi":"10.1136/jitc-2025-011704","DOIUrl":"https://doi.org/10.1136/jitc-2025-011704","url":null,"abstract":"<p><strong>Background: </strong>The tumor microenvironment (TME) poses challenges that limit the efficacy of conventional CAR-T cell therapies. Homing barriers, immunosuppressive factors, and target antigen heterogeneity can impair CAR-T cell functional activity within the TME. Alternative strategies have contemplated incorporating the use of gamma delta (γδ) T cells as a CAR-T cell approach to potentially overcome these limitations. γδ T cells possess both innate and adaptive immunity to facilitate broad tumor recognition, and their natural propensity for tissue tropism may allow for more effective tumor infiltration. Reported here is the preclinical characterization of ADI-270, an allogeneic γδ CAR-T cell product targeting CD70⁺ cancers, engineered with a third-generation CAR based on the natural CD27 receptor. ADI-270 is also double-armored to mitigate the immunosuppressive effects of TGFβ and reduce the potential for allogeneic rejection.</p><p><strong>Methods: </strong>Vδ1 T cells engineered to express an anti-CD70 CAR and dominant negative TGFβ receptor II (dnTGFβRII) were expanded from healthy donor human PBMCs. The phenotype and functional characterization of ADI-270 were assessed with in vitro cell culture assays and in vivo tumor xenograft models.</p><p><strong>Results: </strong>ADI-270 exhibited high levels of in vitro cytotoxicity against a panel of cancer cell lines and displayed a favorable inflammatory cytokine profile compared with reference scFv-based anti-CD70 CAR αβ T cells. Cytotoxicity remained potent despite low CD70 expression observed in multiple solid and hematologic tumor cell models. When armored with dnTGFβRII, ADI-270 exhibited functional resilience to TGFβ-mediated inhibition of T cell effector activity. In addition, the incorporation of potent and sensitive CD70-targeting decreased T cell-mediated alloreactive killing against ADI-270 in vitro without evidence of fratricide. Finally, ADI-270 displayed robust tumor tropism and control of primary and secondary tumor challenges in xenograft mouse models.</p><p><strong>Conclusions: </strong>These results demonstrate the robust potency and capacity of ADI-270 to extend antitumor activity to cancers with heterogeneous antigen expression. The functional armoring incorporated into ADI-270 provides a mechanism to overcome the limitations of reduced efficacy and persistence within the TME. ADI-270 has the potential to target multiple CD70⁺ cancers with initial clinical evaluation proceeding in relapsed/refractory clear cell renal cell carcinoma.</p><p><strong>Trial registration number: </strong>NCT06480565.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 7","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144540277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Low-dose radiotherapy enhances the efficacy of PD-L1 blockade and induces the abscopal effect.","authors":"Pierre-Antoine Laurent, Liu Shi, Lisa Bouarroudj, Nathan Benzazon, Marine Gerbé De Thoré, Winchygn Liu, Marine Aglave, Paul Bergeron, Flavie Naulin, Lisa Sitterlé, Daphné Morel, Antonin Levy, Céline Clémenson, Michele Mondini, Charlotte Robert, Lydia Meziani, Eric Deutsch","doi":"10.1136/jitc-2025-011487","DOIUrl":"10.1136/jitc-2025-011487","url":null,"abstract":"<p><p><b>Background</b> Low-dose radiotherapy (RT) is a promising treatment likely to increase the efficacy of immunotherapy, including programmed cell death ligand 1 (PD-L1) blockade, in cancer therapy. Further exploration and optimization of such combinatorial strategies are required. Notably, the ability of low-dose RT to enhance the efficacy of immune-checkpoint inhibitors (ICI) in distant, unirradiated tumors is debated. <b>Methods</b> We used a stepwise preclinical approach in immunocompetent mice bearing different murine tumor models (MC38 or CT26), with one or two tumors per mouse. Mice received tumor-only irradiation consisting of either low-dose RT (2x0.5 Gy to 2x2 Gy) or high-dose RT (2x6 Gy to 2x8 Gy) combined with anti-PD-L1. Tumor growth rate and survival were compared across the different conditions. The immune microenvironments of both irradiated and distant unirradiated tumors were characterized using single-cell RNA sequencing. <b>Results</b> We first demonstrated that low-dose RT 2×2 Gy combined with anti-PD-L1 is as effective as high-dose RT 2×6 Gy in delaying the growth of irradiated tumors. Subsequently, we showed that low-dose RT to one tumor enhances the efficacy of anti-PD-L1 consolidation therapy in a distant, unirradiated tumor, thereby inducing an abscopal effect comparable to that observed with high-dose RT. Single-cell RNA sequencing analysis highlighted the polarization of tumor-associated macrophages (TAMs) within distant unirradiated tumors towards a pro-inflammatory phenotype following low-dose RT and anti-PD-L1. Depleting TAMs in distant unirradiated tumors using liposomal clodronate abrogated the abscopal effect driven by low-dose RT combined with anti-PD-L1. <b>Conclusion</b> Our findings demonstrate the ability of low-dose RT to increase the efficacy of ICI in a distant tumor, resulting in a significant abscopal effect, and highlight the critical role of TAMs in the underlying mechanism, as well as a potential immune crosstalk between TAMs and activated lymphoid cells. These data propose low-dose RT as a potential strategy to improve the efficacy of immunotherapy in patients with metastatic solid tumors receiving anti-PD-L1.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase II basket trial of Dual Anti-CTLA-4 and anti-PD-1 blockade in Rare Tumors (DART) SWOG S1609: pancreatic neuroendocrine neoplasm (PNEN) cohort.","authors":"Sandip Pravin Patel, Jillian Fisher, Young Kwang Chae, Luisa Solis Soto, Anup Kasi, Bhavana Konda, Mark Walshauser, Edwin Parra, Jiexin Zhang, Caroline Duault, Edgar Gonzalez-Kozlova, Ganiraju Manyam, Jianhua Zhang, Hong Chen, Dzifa Yawa Duose, Caddie Laberiano Fernandez, Raja Luthra, Gheath Al-Atrash, Seunghee Kim-Schulze, Holden T Maecker, Ignacio I Wistuba, Sacha Gnjatic, J Jack Lee, Jianjun Zhang, Christine M Magner, Helen X Chen, Elad Sharon, Megan Othus, Christopher W Ryan, Charles Blanke, Cara L Haymaker, Razelle Kurzrock","doi":"10.1136/jitc-2025-011760","DOIUrl":"10.1136/jitc-2025-011760","url":null,"abstract":"<p><strong>Purpose: </strong>SWOG S1609 <i>D</i>ual <i>A</i>nti-CTLA-4 and anti-PD-1 blockade in <i>R</i>are <i>T</i>umors (DART) studied the efficacy of ipilimumab combined with nivolumab across multiple rare tumor types. We report the results of the pancreatic neuroendocrine neoplasm (PNEN) cohort.</p><p><strong>Experimental design: </strong>Treatment consisted of ipilimumab 1 mg/kg intravenously every 6 weeks with nivolumab 240 mg intravenously every 2 weeks. The primary endpoint was overall response rate (ORR) (Response Evaluation Criteria In Solid TumorsRECIST V.1.1). Secondary endpoints include progression-free survival (PFS), overall survival (OS), and toxicity. Clinical benefit rate (includes ORR plus stable disease (SD)>6 months was examined. Correlative studies were performed. The trial was conducted by the National Cancer Institute/Southwest Oncology Group Early Therapeutics and Rare Cancers Committee and opened at >1,000 sites.</p><p><strong>Results: </strong>19 patients with PNEN were enrolled. The median number of lines of prior therapy was 2 (range: 0-4). The ORR was 11% (2/19 patients); the clinical benefit rate (CBR; stable disease >6 months+partial response+complete response), 26% (5/19). The median PFS was 3 months; median OS, 24 months. The longest PFSs were 26 (intermediate grade PNEN), 31 (low grade) and 39+months (intermediate grade). The most common toxicities were fatigue (47% of patients) and aspartate aminotransferase (AST) elevation (32%); the most common grade 3/4 immune-related adverse event (AE) was AST (32%) and bilirubin elevation (26%), with no grade 5 events. Programmed death-ligand 1 expression by chromogenic immunohistochemistry (N=12 patients assessed) did not associate with ORR; tumor mutation burden (TMB) was high in three patients; one of the two patients with partial remission (PFS=26 months) had high TMB (150 mutations/mb). Peripheral effector memory T-cell activation (N=11 patients assessed by cytometry by time-of-flight with 5 having longitudinal analysis) was associated with response, though the number of patients evaluated was limited.</p><p><strong>Conclusions: </strong>Low-dose ipilimumab plus nivolumab demonstrated an 11% ORR and 26% CBR (includes SD>6 months) in patients with refractory PNEN, with durable benefit (>2 years) in 3 (16%) patients.</p><p><strong>Trial registration number: </strong>NCT02834013.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144528055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Immunotherapy for rapid bone marrow conditioning and leukemia depletion that allows efficient hematopoietic stem cell transplantation.","authors":"Giada Dal Collo, Srdjan Grusanovic, Milad Rasouli, Antoinette van Hoven-Beijen, Yvonne M Mueller, Zara-Li van der Sande, Martin van Hagen, Jan J Cornelissen, Yun He, Yuandong Wang, Emma De Pater, Vincent H J van der Velden, Marc H G P Raaijmakers, Meritxell Alberich-Jorda, Jiuqiao Zhao, Peter D Katsikis, Stefan J Erkeland","doi":"10.1136/jitc-2025-011888","DOIUrl":"10.1136/jitc-2025-011888","url":null,"abstract":"<p><p>Hematopoietic stem cell transplantation (HSCT) is a life-saving procedure to treat hematopoietic disorders. Current bone marrow conditioning protocols create space for healthy donor stem cells by employing irradiation and/or chemotherapy, but carry severe toxicities, resulting in significant morbidity, mortality and substantial long-term complications. To develop a low-toxicity solution, we generated a bi-specific T-cell engager (BTCE) that targets CD117, an abundantly expressed receptor on hematopoietic stem and progenitor cells (HSPC) and leukemia-initiating cells (LICs). We show that the CD117×CD3 BTCE efficiently depletes in vitro and in vivo HSPCs and LICs. The CD117×CD3 BTCE was not toxic and facilitates highly efficient engraftment of human allogenic donor CD34+cells in humanized mice, thereby restoring hematopoiesis in vivo in both normal and leukemia-bearing humanized mice. We demonstrate here that a potent CD117×CD3 BTCE enables rapid HSCT in both benign and malignant conditions.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12207149/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511959","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Annexin A2 to reactivate tumor-associated antigens presentation and relieve immune tolerance in liver cancer.","authors":"Yuxiao Tang, Jianxin Yang, Qicong Shen, Zelong Gao, Mengpu Wu, Chenghua Wu, Jicong Du, Min Li, Changquan Ling, Feng Lu, Yifeng Chai, Xin Dong, Jianxin Qian, Chenqi Li, Feng Xie, Zhenhong Guo, Hui Shen, Dongyao Wang","doi":"10.1136/jitc-2025-011716","DOIUrl":"10.1136/jitc-2025-011716","url":null,"abstract":"<p><strong>Background: </strong>Tumor cells manipulate the tumor-associated antigens presentation to escape immune surveillance; however, the molecular mechanism is not exactly clear and the measure to intervene is missing.</p><p><strong>Methods: </strong>Annexin A2 was knockout by the CRISPR-Cas9 or blocked by the small-molecule matrine, PY60, and hexapeptide. Chemically and genetically induced primary liver cancer models, and the orthotopically implanted liver tumor model were used. Tumor immune environment was analyzed by single-cell sequencing. Annexin A2-interacted proteins and tumor-associated antigens were identified by co-immunoprecipitation coupled with liquid chromatography with tandem mass spectrometry. Tumor cells killing effects were evaluated by co-culture of tumor cells and CD8⁺ T cells.</p><p><strong>Results: </strong>Targeting Annexin A2 effectively suppressed the progression of liver cancer. The immunosuppressive microenvironment was improved by Annexin A2 inhibition in tumor tissues. The CD8⁺ T cells were increased and activated by targeting Annexin A2. Mechanistically, targeting Annexin A2 inhibited its combination with HSP90. The HSP90-mediated tumor-associated antigens presentation was recovered, and the major histocompatibility complex I-presented short peptides were changed, increasing the tumor cells killing by CD8⁺ T cells. Interestingly, Annexin A2 was increased in liver cancer tissues and the overall survival was significantly reduced in patients with high expression. However, Annexin A2 was positively correlated with immune cell infiltration in liver cancer, implying that Annexin A2 was used by tumor cells for immune escape and immunotherapy resistance. Hence, we further confirmed that blocking Annexin A2 increased the therapeutic effects of anti-programmed cell death protein-1 both in vitro and in vivo.</p><p><strong>Conclusions: </strong>Taken together, our results identified the role of Annexin A2 in the tumor-associated antigens presentation and immune evasion, which could be an actionable target in cancer immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12207141/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144505748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping immune activity in HPV-negative head and neck squamous cell carcinoma: a spatial multiomics analysis.","authors":"Natalie Zwing, Lena Voith von Voithenberg, Laurent Alberti, Sascha Michael Gabriel, Josep M Monné Rodriguez, Romi Feddersen, Jean-Philippe Foy, Francesca Damiola, Nicolas Gadot, Pierre Saintigny, Bruno Gomes","doi":"10.1136/jitc-2025-011851","DOIUrl":"10.1136/jitc-2025-011851","url":null,"abstract":"<p><strong>Background: </strong>Head and neck squamous cell carcinoma (HNSCC) exhibits low response rates to immunotherapies, with only about 15-25% of patients responding to monotherapy and 30-45% to combination therapy. This limited effectiveness is attributed to significant intertumor and intratumor heterogeneity, which affects the immunological activity of individual tumors and their regions, thereby influencing immunotherapy outcomes. Various biomarkers at the gene and protein expression levels have been identified to predict the response to immunotherapy in HNSCC.</p><p><strong>Methods: </strong>In this study, we evaluated intertumor heterogeneity using a 27-gene expression signature to stratify tumors by their immunologic activity status. We investigated intertumor heterogeneity at the molecular and cellular level and further analyzed intratumor spatial heterogeneity within and across these subgroups by using spatial multiomics approaches.</p><p><strong>Results: </strong>Immunologically active tumors showed increased interferon-γ and interferon-α signaling and upregulation of major histocompatibility complex-I signaling and genes involved in antigen presentation. Chemokines such as <i>CXCL8</i> and <i>CXCL9</i>, which are crucial for immune cell recruitment, were differentially regulated. The spatial analysis revealed that active tumors tended to show higher autocorrelation of homogeneous regions with immune cell infiltration compared with inactive tumors. Proximity measures showed an increased colocalization of immune cells, particularly CD8+ T cells, T helper cells, and regulatory T cells, near tumor cells in active tumors. Despite this high immune infiltration, HNSCC often has an immunosuppressive microenvironment, which we observed as a colocalization of programmed cell death protein-1+ (PD-1+) cytotoxic T cells and cytotoxic T cells, indicating regional differences in active and exhausted cell ratios. Furthermore, upregulation of JAK-STAT3 signaling in active tumors was potentially associated with immune evasion.</p><p><strong>Conclusions: </strong>The spatial analysis at multiple omics levels allowed for a detailed investigation of molecular and cell type markers to further distinguish between immunologically active and immunosuppressive microenvironments and their spatial heterogeneity. Our study demonstrates that, besides gene expression signatures, cell colocalization signatures can infer immunological activity in HNSCC, thus predicting immunotherapy response.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12198833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144496726","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SITC vision: Opportunities for deeper understanding of mechanisms of anti-tumor activity, toxicity, and resistance to optimize cancer immunotherapy.","authors":"Ryan J Sullivan, Anthony R Cillo, Robert L Ferris, Russell W Jenkins, Harriet M Kluger, Marleen Kok, Evan J Lipson, Luca Paruzzo, William L Redmond, Marco Ruella, Kurt A Schalper, Daniela S Thommen, Keith Tolley, Mark Yarchoan, Charlie Garnett-Benson","doi":"10.1136/jitc-2025-011929","DOIUrl":"10.1136/jitc-2025-011929","url":null,"abstract":"<p><p>Cancer immunotherapy has radically changed the management of several malignancies, and dozens of agents have been approved in the past 15 years. While these advances have changed the field, many challenges lie ahead and must be addressed if we are to optimize the management of cancer with these approaches. A more comprehensive understanding of the mechanisms of action, toxicity, and resistance is needed to guide the next decade of cancer immunotherapy development. To this end, members of the Society for Immunotherapy of Cancer met and identified challenges and opportunities to improve cancer immunotherapy by focusing on the mechanisms by which the specific agents work, the mechanisms of how they cause adverse effects, and the mechanisms of resistance that limit the effectiveness of these agents. The priorities of this effort were to (1) level set by describing the state of the field; (2) describe what is known about how these agents work, fail to work, and cause side effects as well as the key knowledge gaps in these areas and associated challenges for addressing them; (3) provide a patient perspective to highlight the importance of this work to the community most affected; (4) look ahead to the future by identifying and describing prioritized opportunities that the field may focus on to expand the knowledge base of the field and optimize the management of cancer with immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12198810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144496734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systematic identification and targeting of master regulator checkpoints (MRC) governing tumor microenvironment-mediated immune evasion.","authors":"Pasquale Laise, Gideon Bosker, Mariana Babor, Xiaoyun Sun, Stuart Andrews, Lorenzo Tomassoni, Andrea Califano, Mariano Alvarez","doi":"10.1136/jitc-2024-011355","DOIUrl":"10.1136/jitc-2024-011355","url":null,"abstract":"<p><p>Abrogating the immunoevasive role of the tumor immune microenvironment (TIME) represents a critical yet still elusive challenge in cancer treatment. Progress in this area has been hampered by both technological limitations and incomplete understanding of TIME-dependent immunoevasion mechanisms. We hypothesize that the immune-evasive role of TIME subpopulations-including regulatory T cells, cancer-associated fibroblasts, and tumor-associated macrophages-is critically mediated by hyperconnected Master Regulator Checkpoint (MRC) modules whose aberrant activity, as induced by paracrine signals, can be abrogated or modulated either genetically or pharmacologically. MRCs are primarily composed of transcription and co-transcription factors, acting downstream of surface receptors and signal transduction cascades to control the transcriptional identity and, ultimately, the phenotype of individual TIME subpopulations. Pharmacological inhibition of subpopulation-specific MRC proteins can thus help reprogram the TIME and potentially abrogate or modulate its immunosuppressive state. This paradigm shift, away from single ligand/receptor targeting, is supported by recent algorithmic, experimental, and clinical advances allowing systematic identification of MRCs and their pharmacological modulators using systems immunology-based approaches. Refocusing the deployment of existing tools and experimental methods that have proven successful in tumor cell contexts to identify and validate MRC-targeting agents capable of remodeling the immunosuppressive cell states of the tumor microenvironment can potentially pave the road to novel combination therapy synergizing with immune checkpoint inhibitors.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12198795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484450","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}