Cancer immunology research最新文献

{"title":"A Sampling of Highlights from the Literature: Article Recommendations from Our Deputy and Senior Editors.","authors":"","doi":"10.1158/2326-6066.CIR-14-9-WWR","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-14-9-WWR","url":null,"abstract":"","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":"14 9","pages":"1369"},"PeriodicalIF":7.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148872955","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":"Coordinated Immune Activation Following KRAS Inhibition in Syngeneic Models Reveals Molecular Pathways that Potentiate and Limit Antitumor Immunity.","authors":"Daniel R Lu, Tao Osgood, Shining Ma, Huajia Zhang, Matt Kanke, Jessica A Tan, Siddhi N Paudel, Hong Zhou, Juan Estrada, Tracy Yamawaki, Kristin Tarbell, Karen Rex, Jason DeVoss, Scott Martin, Songli Wang, Jude Canon, J Russell Lipford, Angela Coxon, Chi-Ming Li","doi":"10.1158/2326-6066.CIR-25-0794","DOIUrl":"10.1158/2326-6066.CIR-25-0794","url":null,"abstract":"<p><p>Although mutant-specific KRAS inhibitors are approved to treat cancer, a deeper understanding of intratumoral changes driven specifically by KRAS inhibition is needed to maximize therapeutic responses. In this study, we used single-cell RNA sequencing, flow cytometry, and spatial transcriptomics to distinguish mechanisms of tumor control after KRASG12C inhibition [KRAS(G12C)i] or MEK inhibition (MEKi). Despite both inhibiting the MAPK pathway, KRAS(G12C)i and MEKi drive the adaptation of distinct neoplastic cell fates affecting metabolism and cell-cycle regulation, and additive tumor suppression is observed after co-administration. KRAS(G12C)i results in the emergence of a specific, cDC1-driven mature conventional dendritic cell (cDC) state. Coculture of treated neoplastic cells with cDC1s is sufficient to upregulate maturation markers such as CCR7, and intercellular communication analyses suggest that activation is augmented through nonimmune mediators. Both KRAS(G12C)i and MEKi increase infiltration of cytotoxic T cells, but MEKi, which also targets nonmalignant cells, is associated with a reduced capacity for T-cell proliferation and degranulation, consistent with distinct adaptive immune activation mechanisms. We observe that combination treatment of KRAS(G12C)i with anti-PD-1 immunotherapy further expands effector T-cell states, increases clonal persistence, and induces proinflammatory macrophages associated with higher overall survival that were largely absent after KRAS(G12C)i alone. Furthermore, combination treatment enhances intercellular communication networks among non-PD-1+-expressing cells that can perpetuate cDC activation. Our findings delineate distinct tumor and immune responses to KRAS and MEK inhibition and identify molecular features of the responding tumor microenvironment that may be leveraged to improve therapeutic efficacy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1433-1453"},"PeriodicalIF":7.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13535328/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148374716","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":"Cancer-Intrinsic Protein Neddylation Modulates the Intratumoral Immune Landscape to Constrain Immune Checkpoint Blockade Therapy.","authors":"Irineos Papakyriacou, Yonglin Lu, Malin Jarvius, Maris Lapins, Jordi Carreras-Puigvert, Yumeng Mao","doi":"10.1158/2326-6066.CIR-25-1309","DOIUrl":"10.1158/2326-6066.CIR-25-1309","url":null,"abstract":"<p><p>The cancer-intrinsic network controlling the response to immune checkpoint blockade therapy remains elusive. Using a published single-cell RNA sequencing (scRNA-seq) dataset from patients with breast cancer, we found that pretherapy mRNA expression of NEDD8, which encodes the regulatory protein essential for neddylation, in cancer cells was negatively associated with T-cell expansion upon pembrolizumab treatment. Genetic ablation of protein neddylation in murine tumors induced a curative response to PD-1 or PD-L1 blockade in mice. Combined analysis of neddylation-deficient murine tumors using scRNA-seq and high-resolution spatial transcriptomics revealed distinct spatial immune co-localization and immune cell signatures. In a high-content phenotypic screen of known compounds, protein neddylation was required for the induction of phenotypic changes by lipid inhibitors and ferroptosis inducers in human breast cancer cells. In accordance, these compounds enhanced the efficacy of PD-1 blockade and protected mice from tumor rechallenge. Altogether, we delineate the unknown functions of protein neddylation on antitumor immunity and provide therapeutic options that can enhance immunotherapy.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1467-1483"},"PeriodicalIF":7.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13535320/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148301057","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":"ADAR1 Deficiency in Pancreatic Cancer Cells Potentiates cDC1 Activation and Promotes Sensitization to Immunotherapy.","authors":"Botai Li, Xiaoshuang Wang, Bowen Xie, Xuan Zhong, Peng Wei, Xinyi Lou, Ting Zhang, Chen Dong","doi":"10.1158/2326-6066.CIR-25-1626","DOIUrl":"10.1158/2326-6066.CIR-25-1626","url":null,"abstract":"<p><p>Pancreatic cancer responds poorly to immunotherapy, primarily due to poor activation of CD8+ T cells and their limited infiltration into the tumor tissue. Strategies to enhance CD8+ T-cell priming and function are therefore critical for improving immunotherapeutic efficacy in pancreatic cancer. The RNA-editing enzyme adenosine deaminase acting on RNA 1 (ADAR1) plays a pivotal role in maintaining immune homeostasis. In this study, we found that ADAR1 expression positively correlates with pancreatic cancer progression. Depletion of ADAR1 in tumor cells resulted in excessive production of interferon β, which increased the abundance and activation of conventional type 1 dendritic cells. This alteration enhanced CD8+ T-cell recruitment and activation, ultimately sensitizing pancreatic cancer to immunotherapy. Collectively, our findings support ADAR1 inhibition combined with immunotherapy as a promising therapeutic strategy for pancreatic cancer.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1386-1399"},"PeriodicalIF":7.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148270429","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":"Multinucleated Giant Cells in Human Pancreatic Cancer Are a Distinct Macrophage Population Undergoing a DNA Damage Response and Associated with an Aggressive Tumor Microenvironment.","authors":"Marika Viatore, Rebecca Polidori, Anna Rita Putignano, Arturo Bonometti, Daoud Rahal, Marialuisa Barbagallo, Lisa Veghini, Greta Donisi, Gianluca Basso, Desirée Giuliano, Sergio Marchini, Marco Erreni, Maria Rita Fumagalli, Fabio Pasqualini, Fabio Grizzi, Paola Spaggiari, Silvia Uccella, Silvia Bozzarelli, Alessandro Zerbi, Giovanni Luigi Capretti, Vincenzo Corbo, Massimo Locati, Alberto Mantovani, Federica Marchesi","doi":"10.1158/2326-6066.CIR-25-1602","DOIUrl":"10.1158/2326-6066.CIR-25-1602","url":null,"abstract":"<p><p>Macrophages (Mϕ) constitute a dominant and functionally diverse immune population within the microenvironment of pancreatic ductal adenocarcinoma (PDAC), yet how Mϕ heterogeneity contributes to the tumor remains poorly defined. In an institutional cohort of 145 PDAC specimens, we identified a population of multinucleated giant cells (MGC) of Mϕ origin, an entity previously described in chronic inflammation but rarely in cancer. CD68+ MGCs were present in 28% of tumors, enriched in squamous, nonglandular regions, and more frequent after neoadjuvant chemotherapy. By integrating spatial transcriptomics and quantitative imaging, we defined the features of these cells, which, compared with MGCs in nonneoplastic inflammatory lesions, lacked canonical polarization markers (HLA-DR and CD163) and displayed a distinctive transcriptional program characterized by upregulation of the POLR2K, TUBA8, COX5B, and VDAC1 genes, which encode proteins involved in DNA repair, oxidative stress, and MYC signaling. Spatial analyses revealed activation of hypoxia and extracellular matrix-remodeling pathways in MGC-associated niches, and experimental hypoxia promoted MGC formation in vitro. Consistent with these data, we found that in the The Cancer Genome Atlas (TCGA) Pancreatic Adenocarcinoma (PAAD) dataset a Mϕ MGC gene signature was enriched in the squamous PDAC subtype and correlated with poorer overall survival (P = 0.018). Morphometric and immunofluorescence analyses further showed increased 53BP1+Ki67+ nuclei and nuclear atypia in MGCs, indicating ongoing proliferation despite DNA damage. Together, these data identify MGCs of Mϕ origin as an immune cell state shaped by hypoxia and stress signaling, associated with aggressive tumor phenotypes, and potentially exploitable as an immune classifier in PDAC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1370-1385"},"PeriodicalIF":7.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13535325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148350822","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":"In Situ Vaccination, Low-Dose Targeted Radionuclide Therapy, and Immune Checkpoint Inhibition Eradicate Poorly Immunogenic Metastatic Tumors in Murine Cancer Models.","authors":"Trishna Debnath, Won Jong Jin, Ravi B Patel, Peter M Carlson, Md Mahfuzur Rahman, Tracy J Berg, Caroline P Kerr, Rene Welch Schwartz, Yujuan Wang, Meredith Hyun, Irene M Ong, Jamey P Weichert, Reinier Hernandez, Paul M Sondel, Zachary S Morris","doi":"10.1158/2326-6066.CIR-25-1475","DOIUrl":"10.1158/2326-6066.CIR-25-1475","url":null,"abstract":"<p><p>Focal radiotherapy can provide an in situ vaccine (ISV) effect that may prime adaptive antitumor immunity, which can be augmented by combination with intratumoral immune adjuvants and systemic immune checkpoint inhibition. However, propagation of an antitumor immune response is not consistently achieved in metastatic disease. Delivery of low-dose targeted radionuclide therapy (TRT) can promote clonal expansion and propagation of antitumor immune responses. Therefore, in this study, we combined dual immune checkpoint blockade (DCP; anti-PD-L1 and anti-CTLA-4) with ISV (focal radiotherapy with intratumoral injection of tumor-specific monoclonal antibody and IL2) to prime and with low-dose TRT to propagate antitumor immunity. C57BL/6 mice were engrafted with primary and secondary tumors and intravenously injected with tumor cells to model advanced metastatic disease. Mice with poorly immunogenic, syngeneic MOC2 head and neck squamous cell carcinomas or B78 melanomas received monotherapy or double or triple combinations of low-dose TRT, DCP, and primary tumor-targeted ISV. When compared with dual or monotherapies, TRT + DCP + ISV eradicated bulky well-established tumors, prevented development of lung metastases from circulating tumor cells, and extended survival (P < 0.01). TRT + DCP + ISV conferred tumor-specific immune memory, enabling uniform rejection of tumor re-engraftment. TRT + DCP + ISV activated innate and adaptive immune responses in the primary and secondary tumors. Overall, these data highlight TRT + DCP + ISV as a promising approach to prime and propagate antitumor immunity and promote response to checkpoint inhibition.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":"1416-1432"},"PeriodicalIF":7.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13644649/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410455","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":"CD266+ myofibroblasts mediate resistance to immunochemotherapy through ECM stiffness in head and neck squamous cell carcinoma.","authors":"Houyu Ju, Yusheng Lu, Chaoji Shi, Zhiwei Zheng, Yun Bi, Wenyi Yang, Zhaoyang Guo, Mahdi D Dashti, Ming Yan, Guoxin Ren, Jingzhou Hu","doi":"10.1158/2326-6066.CIR-25-1379","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-1379","url":null,"abstract":"<p><p>The efficacy of immunotherapy in unresectable/recurrent/metastatic head and neck squamous cell carcinoma (U/R/M HNSCC) remains suboptimal compared to primary untreated resectable HNSCC. The immunological and stromal landscape during immunotherapy in U/R/M HNSCC is crucial for understanding drug resistance mechanisms. In this study, single-cell RNA sequencing was performed on 42 samples pre- and post-treatment from patients in our prospective trial (NCT05156970) who received immunochemotherapy. A subset of myofibroblasts expressing CD266 was identified in hampering the response to immunochemotherapy in patients with U/R/M HNSCC. This distinct subtype of cancer-associated fibroblasts (CAFs) enhanced extracellular matrix (ECM) stiffness and cellular tension through a Piezo1-mediated biomechanical mechanism, spatially segregated CD8+ T cell infiltration to establish immune-excluded niches, and ultimately facilitated immune evasion. Mechanistically, PIEZO1 inhibition suppressed YAP activation and reduced FAK phosphorylation, thereby mitigating matrix remodeling effects driven by myCAF CD266. We also observed that Piezo1 inhibition had synergistic effect with PD-1 blockade in HNSCC in vivo. In summary, our findings reveal an immunosuppressive mechanism in which stromal cells regulate ECM stiffness, presenting a potential therapeutic target for U/R/M HNSCC.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863721","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":"A High Density of Impaired Tertiary Lymphoid Structures Is Associated with Higher Tumor Stage and Recurrence in Non-Muscle-Invasive Bladder Cancer.","authors":"Sarah Péricart, Marie Tosolini, Mathieu Roumiguie, Axelle Saint, Laetitia Largeaud, Pauline Gravelle, Nathalie Van Acker, Pierre Brousset, Bernard Malavaud, Camille Laurent","doi":"10.1158/2326-6066.CIR-26-0104","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-26-0104","url":null,"abstract":"<p><p>Tertiary lymphoid structures (TLS) have emerged as critical immune niches within the tumor microenvironment across various cancers. However, their structural organization and functional roles in non-muscle-invasive bladder cancer (NMIBC) remain poorly characterized. In this study, we comprehensively characterized TLS in NMIBC using en bloc resected primary diagnostic specimens, which enabled high-resolution spatial mapping and quantitative histological assessment across a large cohort of primary tumors (97 patients). Compared with TLS in inflammation-driven cystitis, tumor-associated TLS showed heterogeneous spatial organization, altered immune composition, and disrupted follicular dendritic cell (FDC) networks with reduced high endothelial venules density. TLS density increased with NMIBC grade and stage and correlated with higher recurrence risk and shorter progression-free survival in multivariable analysis. Paired analysis of primary and recurrent tumors showed a reduction in FDC density and a shift from M1 to M2 differentiation in tumor recurrences, suggesting the development of an immunosuppressive microenvironment. Single-cell RNA sequencing of TLS from NMIBC and cystitis samples revealed impaired germinal center activity in tumor-associated TLS, with asynchronous B-cell maturation and reduced B-cell interactions with both T follicular helper cells and FDC. Tumor-associated TLS also showed increased myeloid infiltration and altered dendritic-cell function, including reduced MHC class II antigen presentation and downregulation of co-stimulatory (CD86-CD28) and migration-related (CD99) pathways compared to TLS from cystitis samples. Overall, we found that NMIBC-associated TLS are structurally and functionally impaired, which may limit effective local immune responses and suggests they may be relevant as biomarkers and targets for immunomodulatory therapy in bladder cancer.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863724","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":"Neutralizing the IL-12/IL-23 p40 subunit prevents immune checkpoint blockade toxicity without compromising antitumor efficacy.","authors":"Christianne Groeneveldt, Disha Vadgama, Anne Onrust-van Schoonhoven, Declan Whyte, Maaike M Hofman, Nina E M Rozendaal, Menno van Nimwegen, Mike Eterman, Daphne W Dumoulin, Ron H J Mathijssen, Arjen Joosse, Astrid A M van der Veldt, Louis Boon, Michail Doukas, Janneke N Samsom, Ralph Stadhouders, Floris Dammeijer, Joachim G J V Aerts, Maria E Joosse","doi":"10.1158/2326-6066.CIR-26-0177","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-26-0177","url":null,"abstract":"<p><p>Immune checkpoint blockade (ICB) has markedly improved overall survival in various cancers, but is associated with severe and sometimes fatal immune-related adverse events (irAEs). Current management of irAEs involves discontinuation of ICB therapy and administration of immunosuppressive drugs, such as corticosteroids, which have been associated with decreased antitumor efficacy. Although irAE development is associated with ICB response, it is currently unknown whether their underlying mechanisms are shared or distinct. To identify early and targetable drivers of irAEs, we performed proteomic analyses on the serum of patients with cancer treated with anti-PD-1 and anti-CTLA-4 combination ICB. We identified a significantly increased concentration of p40, a subunit of IL-12/IL-23, shortly after the start of ICB but before the onset of clinically apparent irAEs. Importantly, increased p40 levels were not associated with ICB efficacy. Neutralizing p40 mitigated ICB-induced toxicity in various mouse models without impairing ICB-induced antitumor efficacy. In conclusion, we demonstrated that IL-12/IL-23p40 is a key mediator of ICB-induced toxicity while being redundant for ICB antitumor efficacy. This shows that the mechanisms underlying ICB toxicity and efficacy can be uncoupled and provides a rationale for p40 blockade in clinical trials with ICB treatment to prevent irAEs in patients.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148863692","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":"EphA4 Mediates Pro- and Antitumoral Effects Through Upstream Negative Regulation of AKT in Head and Neck Squamous Cell Carcinoma.","authors":"Sophia Corbo, Khalid N M Abdelazeem, Diemmy Nguyen, Shilpa Bhatia, Benjamin Van Court, Nicholas A Olimpo, Jacob Gadwa, Chloe A Hodgson, Jessica I Beynor, Von G Samedi, Enrique Sanz-Garcia, Lillian L Siu, Anthony J Saviola, Lynn E Heasley, Elena B Pasquale, Michael W Knitz, Sana D Karam","doi":"10.1158/2326-6066.CIR-25-1353","DOIUrl":"https://doi.org/10.1158/2326-6066.CIR-25-1353","url":null,"abstract":"<p><p>Head and Neck Head and Neck Squamous Cell Carcinoma (HNSCC) is driven by an immunosuppressive tumor microenvironment (TME). We examined the immune-modulatory role of EphA4 in HNSCC using spatial analysis, multi-compartment RNA-sequencing from Oral Cavity Squamous Cell Carcinoma (OCSCC), and three genetically engineered mouse models. Within the HNSCC TME, EphA4 is primarily expressed in Tregs, macrophages, CD8+ T cells, and HNSCC cancer cells. EphA4 in Tregs promotes tumor growth, whereas EphA4 in myeloid cells, CD8+ T cells, and cancer cells limits it. EphA4 mediates these differential effects through shared negative regulation of AKT signaling where its knockout increases AKT activation, leading to reduced Treg immunosuppression, increased M2 macrophage polarization, impaired CD8+ T cell memory differentiation, and enhanced cancer cell proliferation. APY-d3-PEG4, EphA4 inhibitor, reduced tumor growth primarily by targeting Tregs. EphA4 expression on CD8+ T cells correlates with treatment response, representing a potential biomarker, and cell-type-specific targeting via cis-bispecific antibodies offers a promising therapeutic strategy. Interrogating human data shows that EphA4 expression on CD8 correlates to response to treatment, posing it as a potential biomarker for future studies. Mechanistically, our data show EphA4 inhibits AKT signaling, and its inhibition enhances AKT functionality across cell types, yielding opposing effects in cancer.</p>","PeriodicalId":9474,"journal":{"name":"Cancer immunology research","volume":" ","pages":""},"PeriodicalIF":7.9,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148817606","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}