Accurate biomarkers of immune checkpoint blocker (ICB) response remain a need in metastatic muscle-invasive bladder cancer (MIBC); therefore, Goubet and colleagues sought to determine biomarkers to guide use of neoadjuvant ICBs in localized MIBC. Follicular helper CD4+ T cells (TFH) and IgG against urothelium-invasive Escherichia coli were found to direct clinical response such as progression-free survival after pembrolizumab treatment. CXCL13 produced by tumor-localized blood central memory TFH cells was found in the plasma of patients who responded, and IgG3+ CD38+ TFH cells present in bladder tissues were correlated with clinical benefit, suggesting a potential link between tumor infection and the success of ICBs.See article, p. 2280.Distant metastases arise in about half of patients after surgical removal of localized clear-cell renal cell carcinoma (ccRCC) tumors. There remains a need to accurately identify which patients are likely to relapse and to develop effective adjuvant treatments for these patients. Rappold, Vuong, and colleagues performed transcriptomic analysis of tumors from the placebo arm of a negative adjuvant trial and found that a myeloid gene signature correlates with relapse and survival. A novel metastatic ccRCC mouse model was developed and used to show that targeting myeloid inflammation using a small-molecule adenosine receptor inhibitor can effectively reduce metastatic burden.See article, p. 2308.Despite T-cell infiltration levels being correlated with better outcome in pancreatic ductal adenocarcinoma (PDAC), therapeutic strategies aimed at T-cell reactivation have not been successful. Schalck, Sakellariou-Thompson, and colleagues used single-cell RNA sequencing and T-cell receptor analysis to profile 80,000 T cells from pancreatic tumors and cultured tumor-infiltrating lymphocytes (TIL) to investigate T-cell dynamics. Clonal expansion was found almost exclusively in CD8+ TILs, with cell-state trajectory analysis suggesting GZMK+ effector cells transition to either a GZMB+PRF1+ cytotoxic or a CXCL13+ dysfunctional population, with dysfunctional and inhibitory populations often co-occurring. Additionally, analysis of cultured TILs revealed that high-frequency clones from effector populations were preferentially expanded.See article, p. 2330.Intratumoral heterogeneity is a collective consequence of tumor-intrinsic properties and extrinsic immune selection. Lin, Peng, Dong, and colleagues conducted a comprehensive characterization on multiregional samples from 45 patients to delineate the genotypic–immunophenotypic connections in intrahepatic cholangiocarcinoma (iCCA). Based on geospatial immune abundance, patients with iCCA were classified into sparsely, heterogeneously, and highly infiltrated subgroups—each harboring distinct immunogenomic characteristics, neoantigen depletion mechanisms, and treatment strategies. The intimate tumor–immune communications were exemplified by the effect of FGFR2 alterations on shaping an immunosuppressive microenvironment and highlighted by the strong prognostic value of integrating immune infiltration and immunoediting mechanisms.See article, p. 2350.Chimeric antigen receptor T-cell (CART) immunotherapy has led to unprecedented responses in patients with refractory/relapsed B-cell non-Hodgkin lymphoma; however, two thirds of patients experience treatment failure. Lee and colleagues demonstrated that, in patients with lymphoma treated with anti-CD19 CART (CART19), chromosomal alteration of BCL-2 was associated with reduced survival. Since BCL-2 inhibition was found to be toxic to CART cells in vivo, a strategy to make CART cells resistant to venetoclax was devised in which CART19 cells express a mutant form of BCL-2. Combination of these BCL-2–mutant CART cells plus venetoclax dramatically improved tumor control through improved CART survival and persistence, thus improving therapeutic efficacy.See article, p. 2372.Clonal hematopoiesis (CH) correlates with an increased risk of developing myeloid neoplasms, and one of the most frequent mutations in CH targets the epigenetic regulator TET2, which leads to clonal dominance of mutated stem cells. Yeaton, Cayanan, and colleagues developed an animal model of TET2-induced CH, and single-cell profiling of bone marrow from aged animals developing myeloid malignancy demonstrated that disease progression correlates with an enhanced inflammatory response and the emergence of aberrant inflammatory monocytes. Such monocytes originate from the leukemic clone and can potentially influence the immune tumor microenvironment.See article, p. 2392.While immune-modulatory therapies hold promise to improve outcomes for patients with pancreatic ductal adenocarcinoma (PDAC), development of such therapies requires an improved understanding of the immune evasion mechanisms that characterize the PDAC microenvironment. Abrego, Sanford-Crane, and colleagues found that cancer cell–intrinsic glutamic-oxaloacetic transaminase 2 (GOT2) shapes the immune microenvironment to suppress antitumor immunity. Mechanistically, GOT2 functions beyond its established role in the malate–aspartate shuttle and promotes the transcriptional activity of the nuclear receptor peroxisome proliferator-activated receptor delta (PPARδ), which is facilitated by direct fatty acid binding. Independent of proliferation, the GOT2–PPARδ axis promotes PDAC progression by modulating the myeloid and lymphoid compartments of the tumor microenvironment.See article, p. 2414.Recently, an adapter for a Cullin-3 RING E3 ubiquitin ligase complex termed LZTR1 was identified as responsible for degradation of the noncanonical RAS GTPases RIT1 and MRAS. Here, Chen and colleagues determine that loss-of-function alterations in LZTR1 found in clonal hematopoiesis and myeloid neoplasms drive hematopoietic expansion and transformation in vivo. Leukemia-associated mutations in RIT1 similarly resulted in myeloid neoplasms, and hematopoietic transformation downstream of LZTR1 required MRAS. These data identify new oncogenic pathways driven by LZTR1 loss and stabilization of noncanonical RAS GTPases in leukemia as well as illuminate therapeutic means to overcome drug resistance in these settings.See article, p. 2434.Nerves participate in cancer progression, but how they facilitate cancer invasion remains poorly understood. Deborde and colleagues revealed that Schwann cells (SC) activated by cancer cells collectively function as tracks termed tumor-activated Schwann cell tracks (TAST). SCs from TASTs dynamically apply forces on cancer cells to enhance cancer motility, with these SCs being activated by c-Jun, which is a process analogous to their reprogramming during nerve repair. Furthermore, patients with pancreatic ductal adenocarcinoma show correlations between elevated SC gene expression signatures and reduced survival. These findings establish a novel paradigm of how cancer cells co-opt wound repair mechanisms to support invasion.See article, p. 2454.