Engineered probiotic <i>Bifidobacterium</i> for tumor-targeted pancreatic cancer therapy

Pancreatic ductal adenocarcinoma (PDAC) presents a substantial challenge due to its resistance to cancer treatments. This limited efficacy is, in part, attributed to the immunosuppressive tumor microenvironment (TME), which impairs effector T (T eff ) cell activity. Interleukin-2 (IL-2) is a key cytokine for T cell activation, but its therapeutic use is limited by a short half-life, systemic toxicity, and regulatory T (T reg ) activation. To address this limitation, we engineered Bifidobacterium longum , a probiotic obligate anaerobe that selectively colonizes the TME, to continuously secrete Super-mutant IL-2 (SumIL-2), an engineered IL-2 variant that preferentially activates T eff cells over T reg cells, thereby delivering SumIL-2 selectively to the tumor (BifidoSumIL-2). Systemic administration of BifidoSumIL-2 significantly suppressed tumor growth in both subcutaneous tumors and orthotopic PDAC in mice, inducing an improved T eff /T reg ratio. Combining BifidoSumIL-2 with chemotherapy, radiation, and immunotherapy further restrained orthotopic PDAC growth, highlighting its therapeutic potential for difficult-to-treat cancers like PDAC.