ADVANCING TREATMENT FOR TRIPLE-NEGATIVE BREAST CANCER: INTEGRATING PHOTOTHERMAL THERAPY WITH IMMUNOMODULATION IN A PRECLINICAL MODEL

Abstract

Triple-negative breast cancer (TNBC) is an aggressive and highly metastatic form of breast cancer with limited treatment options and poor long-term outcomes. Even when the primary tumor is controlled, relapse, metastatic spread, and treatment resistance remain major challenges. Therefore, there is a critical need for treatment strategies that can eliminate the primary tumor, reduce distant metastasis, and activate long-lasting anti-tumor immune responses. This dissertation focuses on developing and evaluating a targeted, heat-based therapeutic approach combined with immune-based treatment and surgery for TNBC. Using orthotopic 4T1 breast tumor models, this work compared different thermal treatment methods and examined how treatment timing, temperature, and delivery route influenced tumor control, immune activation, metastasis, and survival. The findings showed that mild, localized heating provided the best balance between direct tumor destruction and immune stimulation, especially when combined with immune therapy, local immune activation, and surgical tumor removal. These combination treatments improved survival, reduced metastatic burden, increased anti-tumor T-cell responses, and decreased immunosuppressive immune cell populations. Altogether, this dissertation establishes a preclinical platform for targeted, localized therapy combined with immune modulation and surgery to improve outcomes in aggressive TNBC. This work supports the future development of clinically translatable combination strategies that can treat both local and metastatic disease while promoting systemic anti-tumor immunity.