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

Abstract

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.