Ya Han

Tumor-infiltrating T cell plasticity dictates the efficacy of immune checkpoint blockade. While interferon-imprinted (ISG15+) T cells frequently emerge within the tumor microenvironment, their biological fate—whether acting as terminally exhausted sinks or active precursors—remains controversial. Integrating a pan-cancer atlas of 2.3 million cells across 39 malignancies with epigenomic, spatial, and in vivo profiling, we redefine ISG15+ T cells as an epigenetically poised, transitional reservoir. These stress-adapted cells maintain open chromatin at both cytotoxic and exhaustion loci. Spatially sequestered in the tumor core, they physically juxtapose with proliferating epithelial cells, where LGALS9-CD44 signaling acts as a tether enforcing this stalled state. Crucially, clonal tracking and in vivo models demonstrate that ICB breaks this spatial tethering, driving massive lineage diversion of ISG15+ clones into active effector pools. Consequently, baseline ISG15+ abundance represents a "spring-loaded" reservoir whose initial presence—and subsequent post-treatment clearance—robustly predicts ICB success.

The tumor microenvironment evolves during tumor development and influences the cells in the microenvironment to orchestrate a supportive environment for tumor growth. Here we collected 4,483,367 cells across 36 cancer types and constructed a pan-cancer resource named TabulaTIME. Our integrated analyses reveal that CTHRC1 is a hallmark of extracellular matrix-related cancer-associated fibroblasts (CAFs) that are enriched in different cancer types. Spatiotemporal analyses further indicated that CTHRC1⁺ CAFs are located at the leading edge between the malignant and normal regions, potentially preventing immune infiltration. Moreover, we identified that SLPI⁺ macrophages exhibit profibrotic-associated phenotypes and colocalize with CTHRC1⁺ CAFs to form unique spatial ecotypes. Finally, we demonstrated that TabulaTIME can be used to analyze tumor ecotype composition and can serve as a reference for cell-type annotation. This work establishes a comprehensive single-cell landscape of the heterogenous TME and offers a potential therapeutic strategy for targeting the profibrotic ecotype in cancer treatment.

Bladder carcinoma (BLCA) is characterized by a high rate of post-surgery recurrence and multifocality. Multifocal tumors have a higher risk of recurrence compared to single tumors, significantly impacting bladder cancer-specific mortality. However, the interregional or intraregional heterogeneity within both primary and recurrent tumors remains poorly understood. Here, we employed single-cell RNA sequencing to analyze tumor lesions from five multifocal bladder cancer patients comprising three primary tumors and two recurrent tumors. Our findings revealed that malignant cells derived from recurrent multifocal bladder cancer exhibited higher interregional transcriptional similarity and consistent cellular communication. Furthermore, our analysis uncovered that malignant cells from recurrent tumors may evade immune destruction by suppressing cytokine responses and natural killer cell activity. Notably, we identified a preference for the expression of the tryptophan metabolic enzyme IL4I1 on SPP1⁺ macrophages in recurrent tumors. Functional analyses have revealed that IL4I1 may promotes tumor progression in recurrent tumors by activating the aryl hydrocarbon receptor (AHR) and recruiting regulatory T cells to suppress adaptive immunity. Taken together, our study provides a comprehensive understanding of primary and recurrent multifocal bladder tumors, offering valuable resources for analyzing the multifocality and recurrence of bladder cancer.

ESRRA inhibition is associated with immune infiltrations and proinflammatory signaling in patient tumors.

Kaplan–Meier plots showing progression-free survival and overall survival differences for patients receiving anti-PD1 between the low-risk and high-risk groups defined by the median value of deepBTAS.