Integrative cross-tissue and spatially resolved single-cell profiling uncovers tumour-educated inflammatory remodelling of tissue-resident macrophage ecosystem with immunotherapeutic prognostic significance in pan-cancer.

BACKGROUNDTissue-resident macrophages (TRMs) exhibit dual roles in tumor progression, yet their functional reprogramming within the tumor microenvironment (TME) remains a critical unresolved question.

METHODSWe integrated single-cell and spatial transcriptomics from a pan-cancer atlas of 1.39 million cells across five malignancies with 2,318 bulk RNA-seq samples to investigate macrophage states. A TRM inflammatory remodeling signature (TIR-Sig) was developed for clinical biomarker validation.

RESULTSWe identified a conserved inflammatory TRM subtype (iTRM) characterized by CXCL8/IL1B/IL6 co-expression that correlates with poor clinical outcomes. Crucially, both TRMs and monocyte-derived tumor-associated macrophages (Mono-TAMs) underwent convergent differentiation into functionally similar inflammatory phenotypes, establishing iTRM as a universal tumor-educated state. Further integration analysis revealed an iTRM-enriched TME subtype which featured coordinated infiltration of neutrophils and cancer-associated fibroblasts (CAFs), forming a 'cold tumor' ecosystem associated with immune checkpoint blockade (ICB) resistance and poor prognosis. The derived TRM inflammatory remodeling signature (TIR-Sig) demonstrated dual clinical utility: it predicted patient survival (HR = 19.86, p < .001) and stratified ICB responders (AUC = .706).

CONCLUSIONThis study establishes phenotypic links between tissue-resident and recruited macrophages through inflammatory reprogramming within TME, provides a unifying framework for pan-cancer macrophage plasticity in TME, delivers a clinically actionable biomarker suite (TIR-Sig), and provides potential therapeutic targets for TME remodeling.

KEY POINTSCross-tissue single-cell atlas of tissue-resident macrophages (TRMs). Identification of conserved inflammatory TRM phenotype (iTRM) in pan-cancer. Dynamic convergence of TRM and monocyte-derived macrophage lineages. TRM inflammatory remodelling signature (TIR-Sig) with clinical potential.