From tumor microenvironment orchestrators to actionable targets: a systematic review of TAM-targeted therapies in triple-negative breast cancer.

BACKGROUND

Triple-negative breast cancer (TNBC) is an aggressive subtype lacking estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, with limited treatment options. Tumor-associated macrophages (TAMs), as key immune cells in the tumor microenvironment, exacerbate the malignancy of TNBC by promoting angiogenesis, metastasis, immune evasion, and drug resistance.

METHOD: We systematically searched PubMed, Web of Science, and ClinicalTrials.gov databases to collect clinical trials targeting TAMs for the treatment of TNBC. Data from completed and ongoing studies were extracted and analyzed, focusing on strategies that inhibit macrophage recruitment, clearance, and reprogramming, as well as their combination with standard therapies.

RESULTS

TAMs in TNBC predominantly exhibit an M2-like pro-tumor phenotype, originating from circulating monocytes and tissue-resident macrophages, and drive progression through multiple pathways. Clinical trials indicate preliminary efficacy for strategies including CSF-1/CSF-1R inhibitors, bisphosphonates, and reprogramming agents-particularly when combined with chemotherapy or immune checkpoint inhibitors-though response rates vary, and optimal regimens remain under investigation.

CONCLUSION

TAMs represent a promising therapeutic target in TNBC. Emerging clinical evidence supports the potential of targeted therapies against them, though further optimization of patient selection and combination strategies is required. This review provides a systematic foundation for advancing treatments targeting TAMs. We confirm that the scientific content remains unchanged.