Cancer Cell最新文献

In this issue of Cancer Cell, Zhang et al. show that dual KRAS-EGFR inhibition induces a reversible Paneth-like transition in colorectal cancer, sustaining mitogen-activated protein kinase (MAPK) reactivation through a SMAD1-FGFR3 axis. This reinforces emerging evidence that lineage remodeling underlies early adaptive escape from targeted therapy and carries potential clinical relevance.

Histiocytic neoplasms are clonal disorders of the monocyte/macrophage lineage defined by mutations activating mitogen-activated protein kinase (MAPK) signaling. Recently, the MEK1/2 inhibitor cobimetinib was FDA-approved for patients with adult histiocytoses. Here, aided by a prospective registry of patients with histiocytoses (NCT03329274), we identify that MEK1/2 mutations which constitutively activate MEK independently of RAF are associated with worse progression-free survival with MEK1/2 inhibition as compared to patients with other MEK1/2 mutational classes. The most common RAF-independent MEK1 mutation (MEK1^E102_I103del) drove a lethal histiocytic-like neoplasm in mice, which was sensitive to the ERK1/2 inhibitor ulixertinib. We subsequently treated five MEK1^E102_I103del-mutant patients with ulixertinib on prospective protocols, four of whom were refractory to MEK inhibition. Four of five patients experienced objective responses to ulixertinib. These data reveal the impact of oncogenic MEK mutations in vivo, identify patients with likelihood of resistance to MEK inhibition, and nominate ERK inhibition to overcome resistance to MEK inhibition in histiocytoses.

Spatial omics transforms our understanding of cancer by revealing how tumor cells and the microenvironment are organized, interact, and evolve within tissues. Here, we synthesize advances in spatial technologies that map tumor ecosystems with unprecedented fidelity. We highlighted analytical breakthroughs-including multimodal integration and emerging spatial foundation models-that resolve functional niches and spatial communities, converting spatial patterns into mechanistic insights. We summarize how spatially organized features, from immune hubs to microbiota and neural interfaces, shape tumor evolution and clinical outcomes. We then outline how spatial approaches illuminate precancer biology, metastatic adaptation, and therapy response. Bridging discovery and translation, we provide a practical roadmap for incorporating spatial readouts into clinically oriented study design. We conclude by discussing persistent challenges in standardization and scalability and how high-plex spatial discoveries may be distilled into scalable, AI-enabled, clinically deployable assays, positioning spatial omics as a cornerstone of next-generation predictive and precision oncology.

Despite widespread immune profiling in cancer immunotherapy, the antigen-specific responses that drive clinical outcomes remain poorly defined. In a prospective neoadjuvant trial (NCT04013854) of a single-dose anti-PD-1 (nivolumab) in stage III melanoma, we performed antigen-specific profiling of melanoma and viral-specific CD8⁺ T cells across blood, tumor, and lymph node compartments. Using combinatorial tetramers, we detected melanoma-specific CD8⁺ T cells in 72% of HLA-A1, -A2, and -A3 patients. These cells displayed distinct phenotypes shaped by tissue and antigen context. Tumor-infiltrating T-bet⁺ intermediate exhausted CD8⁺ T cells were strongly associated with pathologic response, while CD39⁺ terminal exhausted cells marked non-response. T-bet and CD39 expression also stratified responses in uninvolved lymph nodes, suggesting early divergence of therapeutic immune trajectories. Longitudinal profiling revealed that circulating melanoma-specific CD8⁺ T cell dynamics was antigen-dependent and associated with clinical outcomes. Our findings highlight the clinical value of antigen-specific profiling and identify mechanistic correlates of anti-PD-1 efficacy.

Tertiary lymphoid structures (TLSs) promote antigen-specific anti-tumor immunity, but the regulators of TLSs homeostasis in cancer remain unclear. Using single-cell RNA-sequencing and spatial transcriptomics, we identify an IGLL5⁺ B cell subset in bladder cancer (BCa). In genetically engineered and humanized mouse models, these IGLL5⁺ B cells disrupt TLS's integrity and impair immunotherapy responses. Mechanistically, IGLL5⁺ B cells bind high endothelial venules (HEVs) via IGLL5-LTβR ligand-receptor interactions, with IGLL5 inducing a conformational change in LTβR that inhibits non-canonical NF-κB signaling, leading to TLSs disassembly. Clinically, blocking IGLL5 preserves TLSs and enhances immunotherapy efficacy in patient-derived xenograft (PDX) and pan-cancer models. Our findings suggest that targeting IGLL5⁺ B cells offers a promising strategy to boost TLS-dependent cancer immunotherapy.

Cancer evolution is a complex and dynamic process, yet most treatment strategies remain static. Infrequent tumor sampling has limited our ability to counteract the transient adaptive states that precede resistance. To address this gap, ARPA-H launched the ADAPT program, an initiative aimed at transforming cancer care by aligning therapies with real-time tumor evolution. Within this framework, the ASCEND-CRC trial aims to uncover early adaptive mechanisms and identify biomarkers to guide therapeutic decision-making in metastatic colorectal cancer (CRC). The study moves beyond single pre-treatment biomarkers by integrating multimodal profiling to longitudinally track tumor evolution and define an actionable set of dynamic biomarkers that inform treatment decisions. Together with other ADAPT initiatives, ASCEND-CRC represents a paradigm shift in precision oncology, establishing a scalable platform to intercept resistance.