Triple-negative breast cancer (TNBC) has historically been challenging to treat due to limited therapeutic options. Since 2018, the treatment landscape has evolved substantially with the approval of precision therapies, including immune checkpoint inhibitors, poly (ADP-ribose) polymerase inhibitors, and antibody–drug conjugates. Despite these advancements, the therapeutic benefit remains limited due to various clinical challenges, largely driven by TNBC heterogeneity and an incomplete understanding of drug–tumor crosstalk mechanisms—both contributing to a restricted pool of eligible patients and variable treatment responses. Concurrently, emerging drugs tested in recent pivotal TNBC trials have demonstrated variable outcomes. Additionally, the associated economic burden has become a pressing global concern, as several approved drugs provide insufficient clinical benefit in relation to high expenditures, often driven by drug pricing. The situation is particularly critical in low- and middle-income countries, where TNBC is highly prevalent, yet access to even chemotherapeutic treatment remains limited. These factors collectively hinder real-world patient outcomes. This review provides a comprehensive analysis of TNBC management, integrating clinical advancements with economic perspectives and raising awareness of underdiscussed topics. The overview presented herein highlights the necessity for a global, interdisciplinary approach and patient centered care in TNBC drug development.

As chimeric antigen receptor (CAR) T cell therapy continues to gain attention as a valuable treatment option against different cancers, strategies to improve its potency and decrease the side effects associated with this therapy have become increasingly relevant. Herein, we report an alternative CAR design that incorporates transmembrane domains with the ability to recruit endogenous signaling molecules, eliminating the need for stimulatory signals within the CAR structure. These endogenous signaling molecule activating (ESMA) CARs triggered robust cytotoxic activity and proliferation of the T cells when directed against the triple-negative breast cancer (TNBC) cell line MDA-MB-231 while exhibiting reduced cytokine secretion and exhaustion marker expression compared to their cognate standard second generation CARs. In a NOD SCID Gamma (NSG) MDA-MB-231 xenograft mouse model, the lead candidate maintained longitudinal therapeutic efficacy and an enhanced T cell memory phenotype. Profound tumor infiltration by activated T cells repressed tumor growth, further manifesting the proliferative capacity of the ESMA CAR T cell therapy. Consequently, ESMA CAR T cells entail promising features for improved clinical outcome as a solid tumor treatment option.