A Sampling of Highlights from the Literature: Article Recommendations from Our Deputy and Senior Editors

Tex have a distinct proteotoxic stress response (from NIH via picryl).T-cell exhaustion limits the efficacy of immunotherapies. To increase understanding of the biology of exhausted CD8+ T cells (Tex), Wang and colleagues have defined the proteomic landscape of Tex in various settings, including mouse models of cancer. A feature of Tex is a unique proteotoxic stress response (PSR), which they term Tex-PSR. Among the characteristics of Tex-PSR is upregulation of specialized chaperone proteins and accumulation of protein aggregates and stress granules. Targeting Tex-PSR chaperones prevents T-cell exhaustion and enhances the efficacy of immunotherapy in preclinical cancer models. A Tex-PSR gene signature correlates with poor immunotherapy response in patients with cancer, emphasizing the clinical applicability of the study.Wang Y, …, Li Z. Nature 2025 Oct 01;DOI:10.1038/s41586-025-09539-1.TET2-mutant CH is associated with improved response to immune checkpoint therapy (from Immcarle151 via Wikimedia Commons).The presence of immune cells derived through clonal hematopoiesis (CH) in solid tumors is typically associated with worse outcomes, but whether it impacts response to immunotherapy is not known. In a mouse model, Herbrich and colleagues find that Tet2 heterozygous mutant CH enhances the response of solid tumors to immune checkpoint therapy (ICT). The tumor-infiltrating Tet2+/mu cells are enriched for antigen-presenting macrophages that effectively cross prime naive CD8+ T cells. The observation that TET2-mutant CH correlates with improved response to ICT in patients with non–small cell lung cancer and colorectal cancer highlights the clinical relevance of the data.Herbrich S, …, Sharma P. Cancer Cell 2025 Oct 16;DOI:10.1016/j.ccell.2025.09.011.Neoadjuvant immunotherapy may provide a new option for non-metastatic colon cancer (from NCI Center for Cancer Research via NCI Visuals).Most nonmetastatic colon cancers are DNA mismatch-repair proficient. Results from a phase II clinical trial conducted by Tan and colleagues suggest neoadjuvant anti–PD-1 plus anti–CTLA-4 immunotherapy may provide a new treatment option for patients with such cancers. Among 31 patients, eight had a response to treatment, including one who had a clinical complete response and did not undergo surgery. Six of the other seven responders had a major pathological response (≤10% residual viable tumor at surgery). Analysis of pre- and post-treatment samples identified several response-associated features, including higher baseline infiltration of CD103+CD8+ T cells with features of dysfunctional/exhausted tumor-reactive cells, providing opportunities to explore biomarkers of response in future studies.Tan PB, …, Chalabi M. Nature 2025 Oct 20;DOI:10.1038/s41586-025-09679-4.CD8+ T cells accumulate in CRATERs in melanoma (From Thomas Hirsch via Wikimedia Commons).It has been challenging to visualize tumor–immune interactions in vivo. In zebrafish endogenous melanoma, Ludin and colleagues observe areas of elevated antigen presentation, which they refer to as Cancer Regions of Antigen presentation and T cell Engagement and Retention (CRATER), at the stroma–melanocyte interface. CD8+ T cells localize to CRATERs, where elevated β2 microglobulin expression by melanocytes allows for prolonged interactions and antigen recognition by CD8+ T cells. TLR9 stimulation enlarges CRATERs, as activated CD8+ T cells accumulate, and they become sites of tumor killing. Human melanomas also harbor CRATERs, and high CRATER density correlates with better responses to immune checkpoint therapy, indicating the importance of these structures.Ludin A, …, Zon LI. Cell 2025 Oct 17;DOI:10.1016/j.cell.2025.09.021.T cells target neoantigen-positive and -negative cancer cells via distinct mechanisms (From Alex Ritter, Jennifer Lippincott Schwartz and Gillian Griffiths via NIH Flickr).How do T cells eliminate neoantigen-expressing tumor cells to prevent cancer? Using a murine sarcoma model with fluorescent neoantigens, Cheung and colleagues demonstrate that T cells prevent the development of ∼50% of sarcomas, whereas ∼100% T cell–deficient mice develop tumors. For tumors that persist in T cell–sufficient mice, silencing of neoantigens on day 5 post-tumor initiation allows tumors to grow, with peak T-cell elimination of neoantigen-positive cancer cells at day 8. IFNγ produced in this process can eliminate neoantigen-negative cancer cells, highlighting that T cells target neoantigen-positive and -negative cancer cells via distinct mechanisms.Cheung JF, …, Joshi NS. Cancer Cell 2025 Oct 02;DOI:10.1016/j.ccell.2025.09.005.MTAP deficiency causes STING agonism resistance (From Emw via Wikimedia Commons).Stimulator of interferon genes (STING) agonists have shown limited activity in human clinical trials despite success in animal models. Hsu and colleagues have identified a possible reason for this discrepancy: Loss of methylthioadenosine phosphorylase (MTAP) deletion occurs frequently in human cancers and rarely in preclinical models. MTAP deficiency causes MTA accumulation, which ultimately leads to inhibition of STING agonist–induced immune cell infiltration through downregulation of interferon regulatory factor 3 (IRF3). The FDA-approved drug DL-α-difluoromethylornithine (DFMO) attenuates MTA accumulation and overcomes STING agonist resistance in preclinical cancer models rendered MTAP-deficient, suggesting ways to improve the use of STING agonists in the clinic.Hsu JM, …, Hung MC. Science 2025 Oct 9;390,eadl4089.