Osimertinib is an effective first-line therapy for EGFR-mutant non–small cell lung cancer, but acquired resistance develops. In ELIOS, a prospective molecular profiling study, Piotrowska and colleagues compared tumor biopsies obtained before treatment and after progression on first-line osimertinib, demonstrating that MET amplification (17%), and EGFRC797S (13%) were the most common resistance mechanisms, while MTAP deletion occurred in 13% and histologic transformation in 10% of tumor biopsies at progression. Using proteogenomic analyses, high TROP2 expression was commonly found at baseline and at progression, irrespective of genetic alterations observed. Only 52 of 91 patients with progression had evaluable tissue biopsies while plasma-based next-generation sequencing underscored the heterogeneity of resistance mechanisms, emphasizing the need for broad-acting treatment strategies after progression on osimertinib.See article, p. 1074.Hong and colleagues performed whole-exome sequencing of 250 tumors from 30 multi-region pancreatic cancer autopsies, which revealed mutually exclusive alterations in the TGF-β pathway. Specifically, SMAD4 inactivation predominated in de novo metastatic pancreatic ductal adenocarcinoma (PDAC), whereas TGFBR2 loss was more common in locally advanced, non-metastatic PDAC, indicating distinct evolutionary trajectories. Functional validation using PDAC organoid models confirmed the differential effects on metastatic potential. While no treatment-attributable driver mutations were identified, irradiated PDACs displayed greater genomic heterogeneity and distinct mutational signatures compared to non-irradiated tumors. These findings highlight SMAD4–TGFBR2 exclusivity as a potential biomarker framework for disease stratification and therapeutic decision-making.See article, p. 1087.Perez-Villatoro and colleagues constructed a comprehensive single-cell spatial proteomic atlas of aggressive ovarian cancer. Employing a custom machine learning tool, CEFIIRA, to integrate spatial, molecular, and survival data, they identified tumor-intrinsic MHCII as a primary determinant of immune ecosystems and prolonged patient survival. In multi-omic and spatial analyses, tumor MHCII expression was linked to enhanced immune activation, spatial immune hotspots, antigen presentation, and T-cell receptor clonality. Patient-derived models further demonstrated that MHCII drives responses to immune checkpoint blockade. These findings position tumor MHCII as a critical predictive biomarker and key candidate for patient selection for immunotherapies in high-grade serous ovarian cancer.See article, p. 1100.By integrating high-dimensional immune profiling with functional validation across patient cohorts, Tran, Cho, Izadmehr, Yoo, and colleagues linked elevated plasma CRP and IL6 to macrophage-driven immune suppression in bladder cancer and defined opposing SPP1+ and CXCL9+ macrophage programs that differentially regulated T-cell activity and response to immune checkpoint blockade. SPP1+ macrophages suppressed T-cell function in part via IL6 signaling, whereas CXCL9+ macrophages promoted immune activation. The balance between these programs predicted immunotherapy response, highlighting a tumor-promoting inflammatory SPP1+ macrophage–IL6–CRP axis that connects systemic inflammation to local immune dysfunction and represents new potential therapeutic targets.See article, p. 1126.Wei, Blaj, and colleagues demonstrated that the combination of a RAS(ON) G12C-selective inhibitor with a RAS(ON) multi-selective inhibitor achieved deeper and more durable suppression of oncogenic RAS signaling (as compared to monotherapies) in preclinical models of KRASG12C-mutant non−small cell lung cancer (NSCLC). This dual combination overcame key resistance mechanisms observed for KRASG12C(OFF) inhibitors, including RAS pathway reactivation driven by receptor tyrosine kinases and KRAS amplification. Notably, increased pathway inhibition, resulting from the doublet enhanced antigen presentation, favorably remodeled the tumor microenvironment, and promoted T-cell infiltration. These changes sensitized immune-refractory lung tumors to immune checkpoint blockade, enabling durable tumor regressions. These preclinical findings highlight the potential for the combination of a RAS(ON) inhibitor doublet, such as elironrasib and daraxonrasib, with immune checkpoint blockade in patients with NSCLC.See article, p. 1152.Infiltrating glioblastoma cells progressively form interconnected tumor networks via neurite-like tumor microtubes and establish malignant neuron–glioma synapses to fuel tumor recurrence, but the key messenger(s) governing glioma–glioma and glioma–neuron crosstalk in this process remains largely elusive. Through multi-omic data mining and functional validation, Ding, Dong, Pan, Liu, and colleagues identified C1QL1 as a pivotal factor secreted from infiltrating glioma cells. C1QL1 orchestrates intercellular crosstalk to simultaneously induce expansion of tumor microtubes and pruning of normal neuronal synapses, facilitating malignant synapse assembly and tumor recurrence via the C1QL1–BAI3–RAC1 signaling axis. Pharmacologic inhibition of RAC1 using a non-GEF–targeting inhibitor effectively impedes recurrence and improves survival in multiple glioblastoma models.See article, p. 1176.Solid tumors often paradoxically increase vascularization while excluding immune cells, a phenotype largely unexplained at the molecular level. Berico and colleagues identified the transcription factor HOXD13 as a master regulator of this process in melanoma. Driving a melanoblast-like developmental program, HOXD13 orchestrates 3D chromatin loops to activate VEGFA, SEMA3A, and CD73. This dual axis simultaneously remodels tumor vasculature and elevates immunosuppressive adenosine, promoting tumor growth and T-cell exclusion. Crucially, combined inhibition of VEGF and adenosine receptors reverses this growth advantage, providing a therapeutic strategy for HOXD13-positive, immune-evasive melanomas.See article, p. 1200.The tumor microenvironment (TME) remains a major barrier to successful immunotherapy. Zhang, Dong, Chow, Xin, and colleagues utilized an in vivo gain-of-function CRISPR activation screen to identify instructive pro-immune gene combinations that reshape the TME. They identified a three-gene cocktail, comprising TNFSF9 (4-1BBL), IFNG, and IL12B, hereafter termed 4II, that enhanced tumor antigen presentation, and T-cell activation, proliferation, cytotoxicity, and infiltration. Delivered via an adeno-associated virus, the 4II payload reprogrammed the TME and synergized with CAR-T and TCR-T therapies to suppress primary and metastatic tumors in vivo. This establishes a rapid route for developing combinatorial immune gene therapies against solid tumors.See article, p. 1222.
A Mon, study studied this question.