Spatial Regulation of Cancer-Associated Fibroblasts and Tumor Cells via pH-Responsive Bispecific Antibody Delivery for Enhanced Chemo-Immunotherapy Synergy.

The effectiveness of chemotherapy is often compromised by physiological barriers and an immunosuppressive tumor microenvironment. Cancer-associated fibroblasts (CAFs) significantly contribute to the reconfiguration of the tumor extracellular matrix (ECM) and the suppression of immune responses, making them crucial targets for therapeutic intervention. Here, a tumor acidic microenvironment-responsive delivery system that utilizes tumor cell-derived microparticles (MPs) as carriers for the chemotherapeutic agent doxorubicin (DOX) and the bispecific antibody YM101 targeting both TGF-β and PD-L1 is developed (DOX@MPs-YM101) to spatially regulate both CAFs and tumor cells for enhanced chemotherapeutic efficacy. DOX@MPs-YM101 efficiently targets tumor tissues and releases DOX@MPs and YM101 in response to the acidic tumor microenvironment. YM101 reprograms CAFs and reduces the tumor ECM, facilitating tumor accumulation and deep penetration of DOX@MPs-YM101. DOX@MPs are highly internalized into tumor cells, triggering immunogenic cell death (ICD) and activating CD8⁺ T cell-mediated antitumor immunity. The reprogramming of CAFs by YM101 further promotes the accumulation of CD8⁺ T cells and reduces the number of immunosuppressive cells within the tumors. Additionally, YM101 effectively neutralizes PD-L1 on tumor cells induced by DOX@MPs, restoring CD8⁺ T cell activity and generating long-term antitumor immune memory to prevent tumor recurrence. Our findings highlight the potential of DOX@MPs-YM101 to improve chemotherapy in cancer treatment.