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Spatiotemporal dynamics of radioresistance: decoding macrophage-driven radioprotective niches through temporal-spatial reprogramming.

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Title: Spatiotemporal dynamics of radioresistance: decoding macrophage-driven radioprotective niches through temporal-spatial reprogramming.
Authors: Zhang M; Department of Radiation Oncology, First Hospital of China Medical University, Shenyang, 110001, People's Republic of China.; Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, People's Republic of China., Zhang X; Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, People's Republic of China., Song X; Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, People's Republic of China., Bai R; Department of Pharmacology, School of Pharmacy, Shengjing Hospital of China Medical University, Shenyang, 110004, People's Republic of China., Qiao Q; Department of Radiation Oncology, First Hospital of China Medical University, Shenyang, 110001, People's Republic of China. braveheart8063@outlook.com., Wei M; Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, People's Republic of China. mjwei@cmu.edu.cn.; Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122, People's Republic of China. mjwei@cmu.edu.cn., Zhao L; Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, 110122, People's Republic of China. lzhao@cmu.edu.cn.; Liaoning Key Laboratory of Molecular Targeted Anti-Tumor Drug Development and Evaluation, China Medical University, Shenyang, 110122, People's Republic of China. lzhao@cmu.edu.cn.
Source: Molecular cancer [Mol Cancer] 2026 Mar 03; Vol. 25 (1). Date of Electronic Publication: 2026 Mar 03.
Publication Type: Journal Article; Review
Language: English
Journal Info: Publisher: BioMed Central Country of Publication: England NLM ID: 101147698 Publication Model: Electronic Cited Medium: Internet ISSN: 1476-4598 (Electronic) Linking ISSN: 14764598 NLM ISO Abbreviation: Mol Cancer Subsets: MEDLINE
Imprint Name(s): Original Publication: [London] : BioMed Central, c2002-
MeSH Terms: Tumor Microenvironment*/radiation effects , Tumor Microenvironment*/immunology , Tumor-Associated Macrophages*/metabolism , Tumor-Associated Macrophages*/immunology , Tumor-Associated Macrophages*/radiation effects , Neoplasms*/radiotherapy , Neoplasms*/pathology , Neoplasms*/metabolism , Neoplasms*/immunology , Macrophages*/metabolism , Macrophages*/immunology , Radiation Tolerance* , Cellular Reprogramming*, Humans ; Animals ; Metabolic Reprogramming
Abstract: Within the intricate tumor microenvironment (TME), tumor-associated macrophages (TAMs) engage in dynamic cross-communication with neighboring cellular and acellular components, orchestrating dual pro- and anti-tumorigenic programs, including tumor proliferation, immune suppression, angiogenesis, extracellular matrix remodeling, and metabolic reprogramming. Radiotherapy, while inducing direct tumoricidal effects, paradoxically triggers vascular injury and inflammatory cascades that recruit and reprogram TAM populations. These radiation-educated TAMs subsequently establish therapy-resistant niches through multifaceted mechanisms, driving post-radiation tumor recurrence and treatment failure. Emerging evidence highlights that TAM polarization states critically determine therapeutic outcomes in both standalone radiotherapy and combination regimens with immunotherapy. However, translating TAM-targeting strategies into clinical practice faces substantial biological and technical challenges.In this review, we systematically analyze the spatial-temporal mechanisms underlying radiotherapy-induced TAM recruitment and radioresistance development, with particular emphasis on their bidirectional interactions with tumor cells, immune effectors, hypoxic niches, and stromal cells. Specifically, we map the therapeutic landscape by evaluating promising targets for TAM reprogramming in combination with radiotherapy and/or immune checkpoint blockade. Furthermore, we critically appraise emerging technologies for TAM manipulation in the radioimmunotherapy context, including nanotheranostics and novel therapeutic approaches. Finally, we discuss unresolved mechanistic questions, translational barriers, and strategic opportunities for developing personalized combination therapies that leverage TAM biology to overcome radioresistance. This synthesis provides a conceptual framework for rationally designing next-generation radiosensitization strategies grounded in TME immunomodulation.
Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests.
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Grant Information: No.82373229 the National Natural Science Foundation of China
Contributed Indexing: Keywords: Combined therapy strategies; Radioresistance; Temporal-spatial cross-talk; Tumor microenvironment; Tumor-associated macrophage
Entry Date(s): Date Created: 20260303 Date Completed: 20260627 Latest Revision: 20260627
Update Code: 20260705
PubMed Central ID: PMC13067690
DOI: 10.1186/s12943-026-02598-6
PMID: 41776613
Database: MEDLINE
Description
ISSN:1476-4598
DOI:10.1186/s12943-026-02598-6