Reprogramming the immune microenvironment in triple-negative breast cancer with mRNA therapeutics

Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous subtype characterized by the absence of estrogen receptor, progesterone receptor, and HER2 expression. Owing to the absence of actionable targets, TNBC patients frequently develop early metastases, experience high rates of recurrence, and show limited responsiveness to conventional therapies. Although immune checkpoint inhibitors provide clinical benefit in a subset of cases, their overall efficacy is inhibited by immune exclusion, antigenic heterogeneity, and a highly immunosuppressive tumor microenvironment. mRNA-based immunotherapies are emerging as a versatile and transformative approach in personalized cancer treatment, designed to elicit durable antitumor immunity against tumor-specific antigens. Their synthetic, transient, and non-integrating nature enables rapid, safe, and patient-tailored therapeutic developments. In TNBC, mRNA platforms are being deployed across three principal strategies: (1) personalized vaccines encoding tumor-associated antigens such as MAGE-A3, NY-ESO-1, or neoantigens derived from TP53 and BRCA mutations; (2) mRNA-engineered immune cells (CAR-T or TCR-T) directed against targets including ROR1, Trop-2, Claudin 6, and Nectin-4; and (3) mRNA-encoded immunomodulators that deliver cytokines (e.g., IL-12, GM-CSF) or costimulatory ligands (e.g., OX40L, 4-1BBL) to reprogram the tumor microenvironment. Nano delivery systems have been central to these advances, protecting mRNA cargo, enhancing cellular uptake, and enabling tumor- or lymphoid-specific targeting. Next-generation nanoparticles are now being optimized to improve tissue specificity, sustain message integrity, and minimize off-target toxicity. This review focuses on future progress in TNBC therapy that relies on integrating precision antigen targeting, immune cell engineering, and advanced delivery technologies. Together, mRNA-based immunotherapies hold immense promise to overcome current therapeutic barriers and pave the way for more effective, personalized treatment strategies in TNBC.