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
Year: 2026
Type: article
Abstract: BACKGROUND: Tissue-resident macrophages (TRMs) exhibit dual roles in tumor progression, yet their functional reprogramming within the tumor microenvironment (TME) remains a critical unresolved question. METHODS: 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. RESULTS: 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). CONCLUSION: 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. KEY POINTS: 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.
DOI: 10.1002/ctm2.70608
Authors: Weikai Wang, Zibin Chen, Yuhan Huang, Zhihao Hu, Peixin Zhu, Zhuoli Huang, Jingzhi Lv, Ziru Liao, Yuhui Zheng, Chen Wei, Baibing Guan, Yin Zeng, Xinyue Zhu, Yafei Yang, Guibo Li, Xin Jin, Xi Chen, Xiao Yang, Zikun Ma, Jianhua Yin
Institutions: BGI Group (China), Chinese Academy of Sciences, University of Chinese Academy of Sciences, BGI Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Zhengzhou University, South China University of Technology, Fujian Medical University, Chinese Academy of Medical Sciences & Peking Union Medical College, Peking Union Medical College Hospital, Zhangzhou Municipal Hospital of Fujian Province, Shanxi Medical University
Language: English
Topic: Immune cells in cancer
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,470
Awards: G340003536, G8074348031, G8371802230
OpenAlex ID: W7128310543