A Sampling of Highlights from the Literature

Cancer-specific RNA splicing yields neoantigens common to multiple cancer types (from Srosenbe via Wikimedia Commons)Cancer-specific RNA splicing events, referred to as neojunctions (NJs), can give rise to neoantigens, but whether specific NJs occur across tumor types is unclear. Through analysis of RNA-sequencing data, Kwok and colleagues identify NJs common to multiple cancer types. Some NJ-encoded peptides are translated, presented by MHC class I, and recognized by T cells. T cells engineered to express a T-cell receptor specific for one such peptide can kill tumor cells, including glioblastoma and melanoma cells, in vitro and patient-derived glioblastoma cells in a xenograft model, highlighting the possibility of T cell–based immunotherapies for use across cancer types.Kwok DW, …, Okada H. Nature 2025 Feb 19;639,463–473.Neutrophils promote breast tumor aggressiveness (from BruceBlaus via Wikimedia Commons)Increased understanding of the cellular interactions that promote breast cancer development and progression could identify new therapeutic targets. Through RNA sequencing of single cells and physically interacting cells at different times during tumor development in the MMTV-PyMT mouse model of breast cancer, Camargo and colleagues find neutrophils physically interact with breast cancer cells in advanced tumors. Functionally, macrophages in the breast tumor microenvironment are shown to recruit the neutrophils, which promote an invasive, proliferative, and proangiogenic program in the breast cancer cells they interact with. In patients with advanced breast cancer, a similar program correlates with worse survival, highlighting the translatability of the study.Camargo S, …, Cohen M. Nat Cancer 2025 Mar 7;6:540–558.IL33 in the tumor-draining lymph node limits the efficacy of cancer therapeutics (from Ed Uthman via Flickr)Many cancer treatments cause tumor-cell apoptosis, but how these apoptotic cells affect antitumor immunity is unclear. Lamorte and colleagues report that treatment with either the chemotherapeutic cisplatin or the BRAF inhibitor PLX4720 induces tumor-cell apoptosis in mouse models of melanoma. Apoptotic tumor cells in tumor-draining lymph nodes are phagocytosed by medullary sinus macrophages (MSM). This induces the MSMs to produce IL33, which activates regulatory T cells that migrate to the tumor and suppress antitumor CD8+ T-cell responses. Adding a blocking antibody targeting the IL33 receptor ST2 to cisplatin or PLX4720 enhances tumor control, indicating that IL33 can attenuate the efficacy of cancer therapeutics.Lamorte S, …, McGaha TL. Cancer Cell 2025 Mar 6;DOI:10.1016/j.ccell.2025.02.017.“Fragile” Tregs adopt a Th1-like program in response to CTLA4, PD-L1 and VEGF triple therapy blockade (via PickPik)Adding vascular endothelial growth factor (VEGF) blockade to immune checkpoint inhibitors improves therapeutic outcomes, but the mechanisms underlying this are incompletely characterized. In preclinical mouse models of cholangiocarcinoma (CCA), Benmebarek and colleagues demonstrate that combination therapy of CTLA4, PD-L1, and VEGF blockade reprograms the TME by inducing a BAFF-mediated proinflammatory B-cell response. This, along with increased IL12 production, reprograms tumor-infiltrating regulatory T cells (Tregs) toward an antitumoral Th1-like “fragile” state. The authors observe skewing of intratumoral Tregs toward a fragile state in CCA patients receiving CTLA4, PD-L1, and VEGF blockade, highlighting the clinical relevance of the mouse data.Benmebarek MR, …, Greten TF. Immunity 2025 Mar 14;58,926–945.Endogenous retroviruses can invigorate T-cell responses in cancer (From Geralt via Wikimedia Commons)The expression of endogenous retroviruses (ERVs) has been related to increased tumor immunogenicity. In clear cell renal cell carcinoma, Jiang and colleagues report HIF2 transcription–mediated expression of relatively intact ERVs. Using humanized murine models and patient kidney cancer samples, the authors identified 22 non-redundant ERV-derived peptides across 11 tumors, 8 of which are tumor-specific and presented on HLA class I molecules, and 3 of which induce antitumoral CD8+ T-cell responses. ERV expression can be induced using an HIF stabilizer, which may provide a way to promote antitumor immunity. The data provide a foundation for potential future development of ERV-specific cancer vaccines or T-cell receptor therapies.Jiang Q, …, Kaelin Jr WG. Cell 2025 Feb 28;188,1807–1827.Ubiquitination of LAG3 inhibits anti-tumoral T-cell function (From Rogerdodd via Wikimedia Commons)A lymphocyte activation gene 3 (LAG3)-blocking antibody has clinical efficacy as a cancer immunotherapy, yet the signaling mechanisms of this receptor are not well understood. Using mass spectrometry, nuclear magnetic resonance analyses, and ubiquitination assays, Jiang et al. report that upon ligand engagement, rapid non-degradative polyubiquitination of LAG3 occurs, which induces the release of the FSALE motif of the LAG3 signaling tail. In in vivo mouse models, LAG3 ubiquitination mediates suppression of antitumor immunity. In patient samples, LAG3 and Cbl co-expression correlates with the efficacy of LAG3 blockade therapy, suggesting it could be a predictive biomarker of response to LAG3 blockade therapy.Jiang Y, …,Wang H. Cell 2025 Mar 17;DOI: 10.1016/j.cell.2025.02.014.