Integrated pathomics and multi-omics analyses identify CXCL8-associated M2-like tumor-associated macrophages as key mediators of the pro-tumor microenvironment in pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy characterized by extensive stromal remodeling and immune suppression. This study aimed to systematically evaluate the biological significance of invasive cell death-related programs in PDAC and to clarify the role of C-X-C motif chemokine ligand 8 (CXCL8) in tumor-associated macrophage (TAM) remodeling and pro-tumor microenvironment formation. By integrating whole-slide image-derived pathomic features with bulk transcriptomic, somatic mutation, single-cell transcriptomic, and spatial transcriptomic data, we found that a pathomics-based prognostic model achieved robust risk stratification in both training and validation cohorts. High-risk tumors exhibited increased mutational burden and more severe immune dysfunction. Single-cell analyses identified CXCL8 as a key candidate gene preferentially expressed in M2-like TAMs. Pseudotime, cell–cell communication, metabolic, and spatial analyses showed that CXCL8.pos.M2-TAMs occupied a later pseudotime-associated state and displayed distinct inflammatory signaling, metabolic reprogramming, multicellular interactions, and enhanced pro-tumor functional scores, despite no increase in the canonical M2 program. Virtual knockout analysis predicted that CXCL8 perturbation may affect immune-regulatory and antigen-presentation programs within M2-like TAMs. CXCL8 may mark a functionally specialized pro-tumor state within M2-like TAMs and may contribute to tumor microenvironment remodeling in PDAC. These findings suggest that CXCL8 may serve as a potential biomarker and therapeutic target for PDAC.