Rewiring the breast cancer immune microenvironment through non-coding RNA-macrophage crosstalk: therapeutic vulnerabilities for immune reprogramming

Introduction One of the foremost clinical challenges to effective breast cancer (BC) immunotherapy is a highly immunosuppressive tumor immune microenvironment (TIME), characterized by abundant M2-like tumor-associated macrophages (TAMs) and exhausted T cells, leading to immune evasion and immunotherapy resistance. Although non-coding RNAs (ncRNAs) have been recognized as regulators of TAM recruitment, plasticity, and tumor-TAM crosstalk, the evidence remains fragmented, with ncRNAs often presented as isolated components rather than constituents of convergent immune-regulatory signaling mechanisms. Methods We undertook a systematic evidence search from PubMed, Web of Science, and Scopus databases for original research studies investigating ncRNA-mediated TAM recruitment and polarization in BC. Results Among the 63 eligible studies, we observed a convergent mechanistic pattern wherein different ncRNA classes, consisting of microRNAs, long non-coding RNAs, and circular RNAs, function through a restricted set of signaling hubs, namely PI3K/AKT/mTOR, JAK/STAT3, NF-κB, TGF-β, and hypoxia-associated pathways. These signaling circuits drive M2-like TAM reprogramming, thereby promoting immune suppression, epithelial-mesenchymal transition, angiogenesis, metastasis, and immunotherapeutic resistance. Conversely, a distinct subset of tumor-suppressive ncRNAs promoted M1-like TAM polarization and enhanced anti-tumor immune response. We also propose an exploratory, hypothesis-generating, semi-quantitative translational prioritization model ranking ncRNAs based on macrophage polarization evidence, mechanistic depth, in vivo validation, functional tumor phenotype, and validation in patient samples. Based on this prioritization, we have outlined a TIME phenotype- based strategy for combining ncRNA targeting with existing therapies for TIME remodeling. Discussion Our review has shown the ncRNA-TAM axis as a key immune-regulatory network that may be targeted to reprogram the BC immune microenvironment, which may facilitate the development of potential future combinatorial immunotherapies aimed at improving immune checkpoint blockade, macrophage-directed therapies, and the development of therapeutic vaccine-based strategies.