Highlighted Research Articles

Abstract

Diffuse large B-cell lymphoma (DLBCL) is typically thought to arise from germinal center B cells, yet the developmental origins of molecular subtypes remain unclear. Pelzer and colleagues identified a distinct extrafollicular trajectory in the BN2 subtype of DLBCL driven by cooperating truncating mutations in SPEN and NOTCH2. These alterations promote expansion of marginal zone–like and memory B cells and are associated with worse outcomes, particularly in females. Mechanistically, aberrant X-linked Toll-like receptor signaling enhanced tumor fitness in female models. Notably, IRAK inhibition selectively impaired these tumors, highlighting a potential precision therapeutic strategy and revealing sex-biased biology in lymphoma pathogenesis.See article, p. 1510.Although TGFβ pathway blockade is often pursued to enhance antitumor immunity in small cell lung cancer (SCLC), Schroeder, Mohindroo, Meinhardt, and colleagues uncover an unexpected tumor-suppressive role for cancer cell–intrinsic TGFβ signaling. Their findings demonstrated that inhibition of TGFβ signaling within SCLC cells can accelerate tumor growth and worsen disease. Mechanistically, intact TGFβ signaling restrained proliferative programs, whereas inhibition of this pathway promoted an aggressive state associated with disease hyperprogression. These findings caution that TGFβ inhibition may have unintended tumor-intrinsic consequences in SCLC and highlight the need for biomarkers that distinguish immune benefits from direct tumor-promoting risks.See article, p. 1529.Zhou, Yan, and colleagues demonstrate that senescent cancer-associated fibroblasts (senCAF) drive early-stage lymph node metastasis in pancreatic cancer through lactate-mediated metabolic–epigenetic rewiring. Lactate from senCAFs induces lactylation of histone 3 lysine 24 in lymphatic endothelial cells, activating serine synthesis, protecting cells from oxidative stress, and ultimately promoting lymphangiogenesis. senCAF-educated lymphatic endothelium recruited CCR4+ regulatory T cells from draining lymph nodes, establishing an immunosuppressive peri-lymphatic niche. The HDAC inhibitor chidamide selectively eliminated senCAFs, disrupted this niche, and sensitized tumors to chemo-immunotherapy. A phase II trial confirmed the safety and efficacy of this triple combination in metastatic pancreatic cancer.See article, p. 1550.Zheng, Zhao, Zhan, Zhuang, Chen, Jiang, and colleagues identified an EGFR–SHC1 fusion subtype in non-small cell lung cancer (NSCLC) that exhibits intrinsic resistance to EGFR tyrosine kinase inhibitor (TKI) monotherapy. Mechanistically, this fusion protein drives oncogenesis through a dual activation mechanism, simultaneously engaging the N-terminal EGFR kinase domain and SRC-mediated phosphorylation of the C-terminal SHC1 fusion partner. This establishes a kinase-independent bypass signaling axis that maintains tumor growth, independent of EGFR inhibition. Consequently, single-agent TKI therapy is insufficient. Remarkably, dual inhibition combining afatinib with the SRC inhibitor dasatinib overcame this resistance, producing dramatic tumor regression in a patient, offering a potentially clinically actionable strategy.See article, p. 1573.Radiation and chemotherapy treatments for childhood cancer are known to predispose to subsequent neoplasm development. In this study, Brady and colleagues analyzed the genomes of 200 subsequent breast, thyroid, and meningioma neoplasms arising decades after childhood cancer treatment. This revealed the potential impact of radiation, nitrogen mustard, and platinum treatment on these genomes, with differing mutational signatures for each. Driver alterations also differed in subsequent neoplasms compared to corresponding de novo tumors, including an enrichment of rearrangement driver alterations in subsequent thyroid and meningioma neoplasms. These findings may guide efforts to prevent or treat subsequent neoplasms.See article, p. 1590.Spatial transcriptomics and proteomics each capture only one component of tissue biology, and merging these analyses on one tissue section without compromise has been a technological bottleneck. Yiu, Chang, Yeo, Qiu, Wu, and colleagues developed IN-DEPTH, a protein-first workflow that uses spatial proteomics to guide RNA capture on the same slide, paired with a computational method, SGCC, to quantify how neighboring cells coordinate. In diffuse large B-cell lymphoma, Epstein–Barr virus reorganized the immune microenvironment, enriching immunosuppressive C1Q macrophages and pushing CD4+ T cells toward dysfunction via a candidate IL27–STAT3 axis. Comprising a broadly accessible approach, IN-DEPTH probes tissue in situ while amassing data for spatial foundation models.See article, p. 1611.Clinically, tumors deficient in DNA mismatch repair (MMR) function exhibit characteristic genotypes including high tumor mutational burden (TMB) and microsatellite instability (MSI). MMR-deficient (MMR-d) tumors commonly benefit from durable responses to checkpoint inhibitor (CPI) immunotherapy. Blagg, Riou, Hervieu, Piumatti, Rodriguez-Plata, and colleagues demonstrated that selective small molecule–mediated inhibition of the MMR protein PMS2 was sufficient to elicit patient-like MMR-d genotypes in cancer cells without evoking cytotoxicity. Inoculation of immunocompetent mice with syngeneic cancer cells pretreated with the first-in-class selective, covalent PMS2 inhibitor NP1867 elicited CPI sensitivity and tumor growth delay.See article, p. 1649.Precision oncology often relies on targeted sequencing panels, potentially missing clinically relevant alterations. In this prospective study of patients with advanced solid tumors lacking standard biomarker-guided options, integrated whole-exome and transcriptome profiling uncovered actionable findings in nearly all cases. RNA sequencing revealed additional therapeutic targets beyond DNA alterations, substantially broadening treatment possibilities. Over one-fifth of patients were matched to molecularly informed therapies with observed clinical benefit. These results support the feasibility and added value of combined genomic and transcriptomic profiling to guide treatment selection, particularly for patients with otherwise limited options.See article, p. 1666.Goyette and colleagues established human preclinical models that accurately reflect clinical HER2-heterogeneous breast cancer, wherein ERBB2-amplified (HER2hi) and ERBB2-nonamplified (HER2lo) cells are present in the same cancer cell line. HER2lo cells drive resistance to the antibody–drug conjugate T-DXd by cooperating with HER2hi cells to fuel post-treatment recurrence of HER2-heterogenous tumors. Consequently, combination therapies that increase the efficacy of T-DXd in HER2lo cells, designed based on targets identified in synthetic lethal CRISPR screens, reduced tumor recurrence. These data highlight the functional and clinical relevance of HER2 heterogeneity, which should be considered in clinical decisions.See article, p. 1691.