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Non-coding RNAs modulate macrophage polarization and immune microenvironment in breast cancer progressionNon-coding RNAs May Help Reprogram Immune Cells in Breast Cancer
Frontiers in MedicinePublished November 4, 2026DOI ↗Editorial oversight: Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease
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Key Takeaway
Note that ncRNAs may modulate the breast cancer microenvironment by promoting either pro-tumor or anti-tumor macrophage phenotypes.
This systematic review synthesizes evidence from 63 eligible studies regarding the role of non-coding RNAs (ncRNAs), including microRNAs, long non-coding RNAs, and circular RNAs, in the breast cancer microenvironment. The review focuses on how these molecules influence tumor-associated macrophages (TAMs) and associated processes such as angiogenesis, metastasis, and immunotherapeutic resistance.
Key findings indicate that ncRNAs function through several signaling pathways, including PI3K/AKT/mTOR, JAK/STAT3, NF-kB, TGF-beta, and hypoxia-associated pathways. Specifically, ncRNAs are shown to drive M2-like TAM reprogramming through specific signaling hubs, which promotes a pro-tumor environment. Conversely, a distinct subset of tumor-suppressive ncRNAs promotes M1-like TAM polarization, which supports an anti-tumor immune response.
The authors note that the current evidence remains fragmented. While the ncRNA-TAM axis represents a potential target to reprogram the breast cancer immune microenvironment and improve immune checkpoint blockade or macrophage-directed therapies, the findings are currently exploratory and hypothesis-generating. These results suggest potential future strategies rather than established clinical protocols.
How this fits prior evidence
This systematic review addresses a gap in understanding the molecular mechanisms of the tumor microenvironment in breast cancer. While prior coverage has established the efficacy of specific treatments like trastuzumab botidotin for HER2-positive metastatic breast cancer and the utility of AI systems for mammography screening, this review focuses on the underlying biological signaling of ncRNAs. It provides a foundational look at how ncRNAs influence macrophage polarization, which may eventually inform the development of more effective immune checkpoint blockade strategies.
Researchers reviewed 63 studies to see how non-coding RNAs (ncRNAs) affect the environment around breast cancer tumors. These ncRNAs are molecules that do not code for proteins but play important roles in how cells behave. The study looked specifically at how they influence macrophages, which are immune cells that can either help fight cancer or help it grow.
The findings show that different types of ncRNAs have different effects. Some ncRNAs promote a pro-tumor environment by helping certain immune cells support the cancer. Other ncRNAs are found to promote an anti-tumor response by encouraging immune cells to fight the cancer. These ncRNAs work through several known biological pathways to influence things like blood vessel growth and how the cancer spreads.
Because the evidence is currently fragmented, these findings are not yet ready to change standard medical treatments. However, the research suggests that targeting the link between ncRNAs and immune cells could one day help improve therapies like vaccines or immune checkpoint blockers. Patients should talk to their doctors about current standard treatments.
What this means for you:
Certain non-coding RNAs may help reprogram immune cells to better fight breast cancer in future treatments.
Common questions
What are non-coding RNAs and how do they affect cancer?
Non-coding RNAs (ncRNAs) are molecules that do not make proteins but help control cell behavior. This study found that different ncRNAs can influence the immune environment of breast cancer. Some ncRNAs help the tumor grow, while others can promote an anti-tumor response by changing how immune cells behave.
Can these findings be used to treat breast cancer right now?
No, these findings are not yet ready for clinical use. The evidence is currently fragmented and the study is intended to generate new ideas for future research. These findings suggest potential future strategies for therapies like vaccines or immune checkpoint blockers rather than established medical protocols.
How do these molecules affect the immune system's response?
The study looked at how ncRNAs influence macrophages, which are a type of immune cell. Some ncRNAs promote a pro-tumor environment, while a specific subset of tumor-suppressive ncRNAs can promote an anti-tumor response. This may eventually help improve how the body's immune system fights the cancer.
IntroductionOne 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.MethodsWe 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.ResultsAmong 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.DiscussionOur 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.
