Igniting cold tumors: reprogramming the tumor immune microenvironment with dual-payload ADCs in combination with PD-L1&4-1BB bispecific antibodies

Background The immunologically “cold” microenvironment of triple-negative breast cancer presents a major obstacle to treatment, conferring resistance to current immunotherapies. Targeting the stimulator of interferon genes (STING) pathway has emerged as a promising strategy to enhance immunotherapy efficacy. Methods In this preclinical study, we leveraged a novel integrated approach by employing a B7-H3-targeted dual-payload antibody-drug conjugate (ADC) to induce innate immune responses and reprogram the tumor microenvironment. Results Our preliminary results indicated that the dual-payload ADC induces immunogenic cell death, leading to the release of double-stranded DNA and subsequent activation of the cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthase-STING pathway in macrophages and dendritic cells. This, in turn, promotes dendritic cell maturation, M1 macrophage polarization, and enhanced T-cell infiltration, effectively converting immunologically “cold” tumors into “hot” ones. Most importantly, the synergistic combination of the dual-payload ADC with immune checkpoint inhibitors (PD-L1 and 4–1BB) not only rapidly bridges innate and adaptive immunity but also elicits a robust long-term immune memory response. Conclusions Collectively, these preliminary results demonstrate that the antitumor efficacy of the dual-payload ADC is mediated through STING pathway activation. This insight opens new avenues for enhancing immunotherapy in B7-H3-expressing solid tumors and paves the way for the clinical translation of next-generation ADC designs.