# 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

## TL;DR

This study reveals how tissue-resident macrophages become inflamed in tumors, leading to poor outcomes and resistance to immunotherapy.

## Contribution

The study identifies a conserved inflammatory macrophage subtype (iTRM) and a clinical biomarker (TIR-Sig) with prognostic and therapeutic implications in pan-cancer.

## Key findings

- An inflammatory TRM subtype (iTRM) marked by CXCL8/IL1B/IL6 co-expression correlates with poor clinical outcomes.
- TRMs and monocyte-derived macrophages converge into similar inflammatory phenotypes in the tumor microenvironment.
- The TIR-Sig biomarker predicts survival and ICB response with high accuracy (HR = 19.86, AUC = 0.706).

## Abstract

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

We 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.

We 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).

This 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.

Cross‐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.

Cross‐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.

Pan‐cancer analysis reveals an inflammatory phenotype remodeling of tissue‐resident macrophages (iTRM) in the tumor microenvironment, which is associated with immunosuppression. Tissue‐resident macrophages and monocyte‐derived macrophages exhibit convergent differentiation toward a similar inflammatory phenotype. iTRM‐enriched ecosystems are associated with poorer prognosis and increased resistance to immune checkpoint therapy, prompting the development of the TIR‐Sig biomarker for both prognostic assessment and treatment prediction.