Tumor microenvironment-driven immune evasion in triple-negative breast cancer: mechanisms, clinical challenges, and therapeutic opportunities

Abstract

Triple-negative breast cancer (TNBC) is an aggressive and clinically challenging breast cancer subtype defined by the absence of estrogen receptor, progesterone receptor, and HER2 expression. Because these classical therapeutic targets are lacking, chemotherapy remains a central systemic treatment; however, TNBC is frequently associated with early recurrence, distant metastasis, immune escape, and therapeutic resistance. Growing evidence shows that these malignant features are strongly shaped by the tumor microenvironment (TME), a complex network of tumor cells, extracellular matrix, stromal cells, immune cells, vascular structures, cytokines, chemokines, and signaling mediators. Compared with hormone receptor-positive breast cancer, TNBC often displays stronger immune infiltration and higher immune-checkpoint activity, suggesting an immune-inflamed phenotype in many cases. Nevertheless, immune-cell presence does not always produce effective antitumor immunity because TNBC can develop PD-L1 upregulation, alternative checkpoint activation, antigen-presentation loss, T-cell exhaustion, macrophage polarization, regulatory T-cell expansion, myeloid-derived suppressor cell recruitment, stromal immune exclusion, hypoxia, metabolic stress, epigenetic regulation, and exosome-mediated immune suppression. This review summarizes TME-driven immune evasion in TNBC, emphasizing molecular heterogeneity, hot and cold immune phenotypes, immunosuppressive cellular networks, PD-1/PD-L1 signaling, stromal barriers, metastatic immune escape, advances in clinical immunotherapy, adverse effects, and emerging TME-directed strategies. Understanding these mechanisms may support rational combination therapies, biomarker-guided patient selection, and individualized immunotherapeutic approaches for TNBC.