A Sampling of Highlights from the Literature

IL27 acts directly on CD8+ T cells to enhance their persistence in tumors and antitumor function (from NIAID via Flickr)Identifying cytokines that can overcome tumor-infiltrating CD8+ T-cell dysfunction could lead to improved patient outcomes. By analyzing TCGA and mouse tumor RNA-sequencing datasets, Bréart and colleagues find that expression of IL27 and EBI3, which encode the two subunits of IL27, correlates with a CTL gene expression signature. In several preclinical tumor models, IL27 acts directly on tumor-infiltrating CD8+ T cells to enhance their persistence and effector function, leading to tumor regression. The clinical relevance of these data is highlighted by the observation that high expression of IL27 and EBI3 correlates with improved overall survival in patients with lung or bladder cancer treated with anti–PD-L1.Bréart B, …, West NR.Nat Immunol2025 Feb 5;DOI:10.1038/s41586-024-08510-w.Personalized neoantigen vaccines induce antitumor T-cell responses (from Rita Elena Serda, Duncan Comprehensive Cancer Center at Baylor College of Medicine via NCI)Data from two phase I clinical trials highlight the potential of personalized neoantigen vaccines. Sethna and colleagues report that at a 3.2-year median follow-up, recurrence-free survival (RFS) had not been reached among the eight pancreatic ductal adenocarcinoma patients in whom a personalized mRNA–lipoplex vaccine against somatic mutation–derived neoantigens (autogene cevumeran) induced neoantigen-reactive T cells; RFS was 13.4 months among the eight patients in whom vaccination did not induce neoantigen-specific T cells. Braun and colleagues report that a personalized, peptide-based, neoantigen-targeting vaccine induced neoantigen-specific T cells in all nine patients with renal cell carcinoma who were treated, and none of the patients had disease recurrence at a median follow-up of 40.2 months.Sethna Z, …, Balachandran V.Nature2025 Feb 19;DOI:10.1038/s41586-024-08508-4.Braun DA, …, Choueiri TK.Nature2025 Feb 5;639:474–82.IL17RA suppresses late-stage colorectal tumor progression (from Urbain Weyemi, Christophe E. Redon, William M. Bonner, NCI Center for Cancer Research, via NCI)IL17 receptor A (IL17RA) signaling promotes early colorectal tumorigenesis. In the azoxymethane-induced model of colorectal cancer (CRC), Denk and colleagues find that IL17RA signaling switches from tumor promotion to tumor suppression once tumors become invasive. Tumor suppression occurs because IL17RA in intestinal epithelial cells limits EGFR-mediated epithelial-to-mesenchymal transition and IL17RA in myeloid cells is required for fungal-induced dectin-1 signaling, which promotes CD8+ T cell–mediated antitumor immunity. Engaging these two pathways with recombinant IL17 and heat-killed Candida albicans sensitizes preclinical CRC tumors to anti–PD-1. The data highlight time- and tissue-dependent effects of IL17RA that impact attempts to target IL17 therapeutically in CRC.Denk D, …, Greten FR.Immunity2025 Feb 28;58:701-715.e8.Reserpine can reduce immunosuppression in colorectal tumor. (From Fred the Oyster via Wikimedia Commons)Most colorectal cancers are resistant to immune checkpoint therapies. He and colleagues report that the lactate receptor HCAR1 signaling pathway promotes immunosuppression in colorectal cancer. They show that HCAR1 is expressed on colorectal cancer cells and induces expression of the chemokines CCL2 and CCL7, which recruit immunosuppressive CCR2+ polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) to the tumor. In preclinical models, Hcar1 knockout reduces CCR2+ PMN-MDSC recruitment, increases CD8+ T-cell effector function, and reduces tumor growth. The FDA-approved antihypertensive reserpine, which inhibits HCAR1, has similar effects to Hcar1 knockout and also sensitizes colorectal tumors to anti–PD-1. Targeting HCAR1-mediated PMN-MDSC recruitment may improve colorectal cancer immunotherapies.He J, ..., Lu W.Nat Immunol2025 Feb 4;26:391–403.CAR-M therapy can remodel the TME of solid tumors. (From Donald J. Davidson, University of Edinburgh via Flickr)CAR-macrophage therapies (CAR-M) have potential to infiltrate solid tumors and remodel the tumor microenvironment (TME). In a first-in-human phase 1 clinical trial, Reiss and colleagues administered CT-0508, a CAR-M therapy targeting human epidermal growth factor receptor 2 (HER2), in patients with previously treated, metastatic HER2-overexpressing solid tumors, including breast cancer and gastroesophageal cancer. The authors report CT-0508 is safe and tolerable in 14 patients, as observed by the lack of dose-limiting toxicities, severe cytokine release syndrome (CRS), or immune effector cell-associated neurotoxicity syndrome (ICANS). The CAR-M therapy also increases T-cell recruitment, cytotoxic activity, and clonality, showing that it can remodel the TME.Reiss K.A., ..., Abdou Y.Nature Medicine2025 Feb 7;DOI:10.1038/s41591-025-03495-z.DN3 MBC accumulation in solid tumors is associated with worse outcomes (From NIAID via Flickr)Understanding of the roles of different memory B-cell (MBC) subsets in solid tumors is limited. Ruffin and colleagues report that extrafollicular (EF)-derived CD11c–CD21– double-negative 3 (DN3) MBCs are enriched in the blood and tumors of head and neck squamous cell carcinoma (HNSCC) patients. These DN3 MBCs are hyporesponsive to antigen stimulation, produce low amounts of antibodies, and have lower differentiation potentials. The DN3 MBCs are also associated with advanced disease and worse therapeutic outcomes for patients. These cells exhibit a phenotype similar to EF-derived DN3 MBCs in other chronic inflammatory diseases like infections and autoimmunity.Ruffin A.T., ..., Bruno T.C.Sci Trans Med2025 Feb 19;17:eadh1315.