Probiotic-Driven Therapeutic Vaccine for in Vivo Reprogramming of Tumor Cells To Elicit Postoperative Antitumor Immunity

Postoperative immunosuppression and residual tumor cells critically limit the effectiveness of cancer immunotherapies, including tumor-cell-based vaccines, which often suffer from insufficient immunogenicity and suboptimal cytotoxic T lymphocyte activation. Reprogramming tumor cells into antigen-presenting cells in situ offers a promising self-vaccination strategy, yet efficient and targeted delivery remains a major obstacle. Here, we developed a probiotic-driven therapeutic vaccine platform by engineering the obligate anaerobic probiotic <i>Bifidobacterium longum</i> (BL21) loaded into autologous tumor cells (BL21@Tc) under anaerobic conditions. This system exploits tumor-targeting membrane fusion to deliver BL21 selectively to postoperative residual tumor cells. Activation of intracellular BL21 disrupts cholesterol metabolism, triggering the in vivo reprogramming of tumor cells into a type 1 conventional dendritic cell. These antigen-presenting cell-like tumor cells exhibit enhanced antigen presentation and robustly activate tumor-specific cytotoxic T lymphocytes, effectively remodeling the immunosuppressive postoperative microenvironment. In murine postoperative cancer models, BL21@Tc elicited potent and durable systemic antitumor immunity, significantly inhibiting tumor recurrence and metastasis. Furthermore, BL21@Tc synergized with radiotherapy to improve therapeutic outcomes. This study establishes an innovative anaerobic probiotic-driven platform for in situ antigen-presenting cell reprogramming, offering a powerful strategy for next-generation cancer vaccines targeting postoperative immunosuppression and residual disease.