新辅助化疗诱导PDAC肿瘤微环境发生临床上不同的空间重塑

Neoadjuvant chemotherapy (NACT) followed by surgical resection is increasingly becoming the standard treatment paradigm for pancreatic ductal adenocarcinoma (PDAC). However, post-surgical therapeutic strategies remain largely unguided by tumor. To address this critical gap, we performed an integrated multi-omics analysis using matched tumor specimens from the same clinical cohort (n=18 patients per group) to define how NACT reshapes stromal architecture and antitumor immunity in PDAC.Spatial transcriptomic analysis revealed pronounced NACT-induced reorganization of tumor and stromal compartments. Basal-like and classical-like tumor programs formed distinct spatial domains accompanied by heterogeneous CAF niches, including myCAF-, iCAF-, and apCAF-like regions. Although overall cellular composition was largely preserved, NACT triggered marked subtype-specific remodeling: basal-like tumors exhibited activation of inflammatory signaling, whereas classical-like tumors showed reduced KRAS signaling and epithelial-mesenchymal transition activity. In stromal compartments, myCAF-like regions displayed suppression of collagen biosynthesis and ECM organization programs, while iCAF- and apCAF-like niches retained inflammatory transcriptional states. Notably, NACT selectively increased spatial proximity between CD8⁺ T cells and classical-like tumor regions, whereas basal-like tumors remained embedded within CAF- and myeloid-enriched immune-restrictive microdomains.Proteomic profiling supported these spatial findings by demonstrating coordinated stromal reprogramming after NACT, with increased abundance of collagen- and coagulation-related proteins and reduced proliferative signatures. Cross-modal integration further revealed concordant activation of ECM remodeling pathways in CAF-rich niches and immune-modulatory programs near tumor regions. Consistently, multiplex immunohistochemistry demonstrated significantly increased infiltration of CD8⁺ cytotoxic and CD4⁺ helper T cells with enhanced proximity to malignant epithelial regions, while FOXP3⁺ regulatory T cells remained largely unchanged. Spatial immune organization was clinically relevant, as tumor proximity to activated CD8⁺ T cells predicted superior survival, whereas association with MDSC-dominant niches correlated with poor outcome.NACT therefore reshapes the PDAC microenvironment into clinically actionable spatial states, enabling post-surgical patient stratification and providing a rationale for personalized adjuvant strategies, including immunotherapy and CAF-targeted treatments strategy.