Breast cancer is characterized by insidious onset, rapid progression, easy recurrence, and metastasis. Conventional monotherapies are usually ineffective due to insufficient drug delivery. Therefore, the combination of multimodal therapy with tumor microenvironment (TME)-responsive nanoplatforms is increasingly being considered for the targeted treatment of breast cancer. We synthesized bioactive hybrid nanoparticles for synergistic chemotherapy and photothermal therapy. Briefly, doxorubicin (DOX) and indocyanine green (ICG)-loaded nanoparticles (DI) of average particle size 113.58 ± 2.14 nm were synthesized, and their surface were modified with polydopamine (PDA) and attached to the anaerobic probiotic Bifidobacterium infantis (Bif). The bioactive Bif@DIP hybrid showed good photothermal conversion efficiency of about 38.04%. In addition, the self-driving ability of Bif allowed targeted delivery of the PDA-coated DI nanoparticles (DIP) to the hypoxic regions of the tumor. The low pH and high GSH levels in the TME stimulated the controlled release of DOX and ICG from the Bif@DIP hybrid, which then triggered apoptosis of tumor cells and induced immunogenic cell death (ICD), resulting in effective and sustained anti-tumor effect with minimum systemic toxicity. Thus, the self-driven Bif@DIP hybrid is a promising nanodrug for the targeted chemotherapy and photothermal therapy against solid cancers.