A Sampling of Highlights from the Literature

Transfer of mitochondria with mtDNA mutations from cancer cells to TILs impairs antitumor immunity (from Darryl Leja, NHGRI via Flickr)Mitochondrial dysfunction in tumor-infiltrating lymphocytes (TILs) impairs antitumor immunity. Ikeda and colleagues find a role for cancer cells in this process, showing that cancer cells can transfer mitochondria, including mitochondria with mitochondrial DNA (mtDNA) mutations, to TILs. The transfer of mitochondria with mtDNA mutations from cancer cells to TILs is mediated by direct cell–cell contact through the formation of tunnelling nanotubes and indirectly through small extracellular vesicles. Such transfers cause mitochondrial dysfunction in the TILs, leading to impaired functionality in vitro and in vivo, including impaired responsiveness to immune checkpoint inhibitors. The data provide new insight into mechanisms of cancer immune evasion.Ikeda H, …, Togashi Y. Nature 2025 January 22;638:225-236.The most aggressive form of glioblastoma is characterized by E-MDSCs and M-MDSCs (from Nephron via Wikimedia Commons)Increased understanding of the myeloid-cell populations that comprise most glioblastoma-infiltrating immune cells is needed to target them therapeutically. Using single-cell RNA sequencing to analyze a range of low- to high-grade adult gliomas, Jackson and colleagues identify two myeloid cell subsets unique to IDH-WT grade 4 glioblastoma, the most aggressive form of the disease: early myeloid-derived suppressor cells (E-MDSCs) and monocytic MDSCs (M-MDSCs). E-MDSCs colocalize with a population of stem-like glioblastoma cells and express genes encoding tumor growth–promoting factors, including FGF11. Among patients with IDH-WT glioblastoma, those with a high E-MDSC gene signature had worse overall survival, highlighting the importance of these cells in the disease.Jackson C, …, Pardoll D. Science 2025 January 17;387:eabm5214.T-cell receptor avidity influences T-cell functionality (from Anriar∼commonswiki via Wikimedia Commons)How the avidity of the T-cell receptor on endogenous CD8+ T cells for neoepitope–MHC-I complexes influences tumor control is ill-defined. By analyzing CD8+ T cells with a range of avidities for naturally occurring neoepitopes of the murine sarcoma Meth A or the murine colon adenocarcinoma MC38-FABF, Singhaviranon and colleagues show that low-avidity CD8+ T cells mediate tumor control and immune checkpoint–inhibitor responsiveness. High-avidity CD8+ T cells express higher levels of exhaustion markers. Consistent with these preclinical data, high-avidity CD8+ tumor-infiltrating lymphocytes (TILs) in human cancers are more exhausted, and patients responsive to immune checkpoint inhibitors have significantly higher proportions of low-avidity CD8+ TILs.Singhaviranon S, …, Srivastava PK. Nat Immunol 2025 January 09;26:240–251.IL-33 induces TLS formation (From Laberm67 via Wikimedia Commons)What drives the formation of tertiary lymphoid structures (TLSs)—organized lymphoid aggregates that can form in the tumor microenvironment—is unclear. Amisaki and colleagues report that IL33, an alarmin present in inflamed tissues, modulates the formation of TLSs. In a mouse model of pancreatic ductal adenocarcinoma (PDAC), IL33 induces TLS formation by activating KLRG1+ group 2 innate lymphoid cells (ILC2s) expressing lymphotoxin. These ILC2s migrate from the gut and are modulated by gut microbiota. Administration of an engineered recombinant human IL33 induces ILC2-mediated TLS formation and antitumor activity in a mouse model of PDAC, suggesting a way to harness this knowledge therapeutically.Amisaki M, ..., Balachandran V.P. Nature 2025 January 15; DOI:10.1038/s41586-024-08426-5.Bile acids have immunomodulatory roles (From Atlas of Medical Foreign Bodies via Wikimedia Commons)Bile acids primarily modulate lipid metabolism but can also impact immune-cell functions. Varanasi and colleagues demonstrate that both primary conjugated and secondary bile acids (BAs) have immunomodulatory roles in liver cancer. Patients with hepatocellular carcinoma have elevated levels of the bile acid–conjugating enzyme bile acid-CoA:amino acid N-acyltransferase (BAAT). Deletion of BAAT in preclinical models of liver cancer improves antigen-specific T-cell responses, reduces tumor growth, and enhances anti–PD-1 therapy efficacy. Mechanistically, secondary BAs cause endoplasmic reticulum stress, which promotes T-cell dysfunction, except for ursodiol, which enhances T-cell function. Dietary supplementation with ursodiol improves T-cell antitumoral activity and may be a potential therapeutic avenue.Varanasi S.K., ..., Kaech S.M. Science 2025 January 9;387:192–201.Cholesterol affects plasma membrane organization (From Yale Rosen via Wikimedia Commons)The metabolic activity within immune cells can impact tumor progression. Belabed and colleagues report that cholesterol metabolism impacts conventional dendritic cell (cDC) maturation, thereby influencing antitumoral activity of T cells. The authors show that cholesterol held in reservoirs within cDCs, is utilized by these cells during maturation. The mobilization, trafficking, and organization of cholesterol into lipid nanodomains on the plasma membrane allows the cDCs to better present antigen to T cells. Mechanistically, lipid nanodomain formation is dependent on cholesterol transport through NPC1, which itself is regulated by AXL. Deleting AXL enhances cDC maturation, which improves tumor control, suggesting a potential new avenue for cancer immunotherapy.Belabed M, …, Merad M. Nature Immunology 2025 January 21;26:188–199.