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Abstract. Cancer-associated fibroblasts (CAF) generate an extracellular matrix (ECM) which provides a repository for factors that promote pancreatic cancer progression. Here, we establish that CAF con...

Cell Death & Disease - Loss of CD44 re-educates pancreatic cancer-associated fibroblasts modulating their fibrotic and immunosuppressive functions

Abstract. Cancer-associated fibroblasts (CAF) generate an extracellular matrix (ECM) which provides a repository for factors that promote pancreatic cancer progression. Here, we establish that CAF con...

The tumor microenvironment plays a key role in cancer progression and therapy resistance, with cancer-associated fibroblasts (CAFs) contributing to desmoplasia, extracellular matrix (ECM) remodeling, and elevated interstitial fluid pressure, all of which hinder drug delivery. We investigated fibroblast activation protein–targeted (FAP-targeted) near-infrared photoimmunotherapy (NIR-PIT) as a strategy to improve drug penetration in CAF-rich tumors. In clinical esophageal cancer samples, FAP expression strongly correlated with increased collagen I, hyaluronic acid, and microvascular collapse. CAF-rich 3D spheroids demonstrated elevated ECM deposition and significantly impaired drug uptake compared with CAF-poor models. FAP-targeted NIR-PIT selectively reduced CAFs, reduced ECM components, and restored drug permeability. In vivo, FAP-targeted NIR-PIT enhanced the accumulation of panitumumab and Abraxane in CAF-rich tumors and improved antitumor efficacy when combined with chemotherapy. These findings highlight FAP-targeted NIR-PIT as a promising therapeutic approach to remodel the tumor stroma and overcome drug resistance in desmoplastic solid tumors.

HmmyCAFs may form a triple immunosuppressive niche: possibly secrete ECM (POSTN, etc.) as physical barriers to block CD8⁺ T cells, induce CD8⁺ T exhaustion via those molecules, and use HIF-1α-driven metabolism to create acidic, nutrient-poor microenvironments that suppress T cells. Abstract Hepatocellular carcinoma (HCC) exhibits profound spatial heterogeneity driving therapeutic resistance, while the role of cancer-associated fibroblasts (CAFs) in orchestrating immunosuppressive niches remains incompletely defined. This study integrates single-nucleus RNA sequencing (snRNA-seq) and spatial transcriptomics (stRNA-seq) to map the cellular and molecular landscape of HCC. snRNA-seq identifies key cell populations—including fibroblasts, T_NK cells, and endothelial cells—using canonical marker genes. Spatial transcriptomics maps gene expression across tumor regions (core, invasive front, stroma) via the robust cell type decomposition (RCTD) algorithm. Immunofluorescence validates collagen deposition and POSTN spatial distribution, confirming T-cell exclusion patterns. The analysis identifies hypoxic metabolic myofibroblasts (hmmyCAFs) as central regulators of the tumor microenvironment. hmmyCAFs enrich at the invasive front, forming collagen-rich barriers that physically exclude CD8⁺ T cells. Simultaneously, they secrete POSTN to suppress immune checkpoint signaling and drive hypoxia-mediated glycolytic reprogramming of T-cell metabolism. Clinically, hmmyCAF activity and POSTN expression correlate with reduced progression-free survival and immunotherapy resistance. This multimodal study defines hmmyCAFs as triple architects of physical immunosuppression, molecular regulation, and metabolic remodeling. By linking collagen remodeling, POSTN-mediated checkpoint inhibition, and hypoxia-driven metabolic reprogramming to clinical outcomes, hmmyCAFs and POSTN may serve as potential indicators for evaluating the efficacy of immunotherapy in HCC.

Abstract. Lymph node metastasis (LNM) in early-stage PDAC predicts systemic dissemination and poor survival, yet its underlying mechanisms remain elusive. Here, we demonstrated that senescent cancer-a...