Emerging Protein Targets in Triple-Negative Breast Cancer: Beyond Conventional Therapy

Triple-negative breast cancer is one of the most aggressive types of breast cancer and is especially difficult to treat because it does not respond to standard therapies. Although chemotherapy and some immune-based treatments can help certain patients, many tumors eventually stop responding. As a result, there is an urgent need to identify new treatment strategies that are more effective and long-lasting. This review describes recent progress in understanding how triple-negative breast cancer grows and survives, and how this knowledge is being used to develop new therapies. It covers treatments that help the immune system attack cancer cells, drugs that target weaknesses in cancer cell DNA repair, and antibody-based therapies that deliver toxic agents directly to tumors. The review also explains how large-scale molecular studies are revealing new drug targets and how the tissue surrounding the tumor affects treatment success. Finally, it highlights innovative radiation approaches designed to work together with modern drug therapies to improve patient outcomes.Abstract Triple-negative breast cancer (TNBC) remains one of the most aggressive and therapeutically challenging breast cancer subtypes, lacking expression of estrogen receptor, progesterone receptor, and HER2. Conventional chemotherapy and immune checkpoint inhibitors provide some benefit, but resistance and relapse are frequent. The search for novel targets has therefore become central to developing more effective and durable therapies. Recent advances in proteomics, structural biology, and targeted protein degradation are rapidly expanding the repertoire of actionable molecules in TNBC. This review summarizes current and emerging therapeutic strategies for TNBC, with a focus on targeted approaches designed to address tumor heterogeneity and resistance mechanisms. To this end, recent advances in targeted therapies are examined, including immune checkpoint inhibitors, PARP inhibitors, Trop-2-directed antibody-drug conjugates, anti-angiogenic agents, PI3K/Akt/mTOR pathway inhibitors, androgen receptor antagonists, and CDK4/6 inhibitors, highlighting results from completed and ongoing clinical trials. In addition, we explore novel targets identified through integrative omics approaches, as well as the role of the tumor metabolism and microenvironment in modulating therapeutic efficacy. Finally, we outline innovative radiotherapy strategies based on targeted radiation delivery and biological integration with systemic therapies. Collectively, this review provides an updated and novel overview of the evolving TNBC therapeutic landscape and highlights promising directions for the development of next-generation, biomarker-driven treatment strategies aimed at improving patient outcomes, maintaining a broad perspective on a very large class of targets.