Tumor-infiltrating lymphocytes in triple-negative breast cancer: molecular mechanisms, spatial regulation, and therapeutic implications

Triple-negative breast cancer (TNBC) represents a profound therapeutic challenge due to its aggressive nature and limited treatment options. This review synthesizes recent advances in understanding the TNBC tumor immune microenvironment (TIME), moving beyond the simplistic “cold” tumor paradigm to depict it as a complex, integrated ecosystem. We detail how multilayered networks, including dynamic metabolic cross-talk, transcriptional reprogramming, cancer-associated fibroblasts (CAFs) heterogeneity, and spatial architecture, collectively shape antitumor immunity and determine the efficacy of tumor-infiltrating lymphocytes (TILs). While significant progress has been made, we critically examine the substantial translational gaps that remain, as many insights are still derived from preclinical models. We argue that rationally designed combinations, including the repurposing of clinically approved drugs, offer a near-term pragmatic pathway. Furthermore, we explore the conceptual shift from purely inhibitory strategies toward the selective overactivation of immune or metabolic pathways as a means to address current therapeutic challenges. Finally, we emphasize that the integration of high-dimensional data, including CAF taxonomy, immune phenotyping, and spatial mapping, is pivotal for the development of truly precision immunotherapies. This review concludes that the convergence of these approaches is forging a more comprehensive and actionable framework for the next generation of patient-tailored TNBC treatments.