Gel-FOLactis hydrogel vaccine synergizes with radiotherapy to transform pancreatic cancer microenvironment from 'cold' to 'hot'

Pancreatic cancer remains a highly lethal malignancy, with conventional treatments often falling short due to its aggressive nature and immunosuppressive tumor microenvironment. While immunotherapy offers promise, its efficacy in pancreatic cancer is limited by poor antigen presentation and rapid degradation of immune adjuvants. Radiotherapy can induce immunogenic cell death (ICD), releasing tumor antigens, but the subsequent immune response is often insufficient. There's a critical need for strategies that can amplify antigen presentation and sustain immune activation to convert the

Researchers developed an in situ hydrogel vaccine, Gel-FOLactis, designed for sustained intratumoral delivery. This vaccine utilizes a thermosensitive P407 hydrogel to encapsulate engineered Lactococcus lactis (FOLactis). The engineered bacteria continuously release the immune-stimulating cytokines Fms-like tyrosine kinase 3 ligand (Flt3L) and the co-stimulator OX40 ligand (OX40L). The Gel-FOLactis vaccine was administered in combination with 8Gy radiotherapy to evaluate its synergistic anti-tumor effects and immune modulation.

The sustained release of Flt3L from the Gel-FOLactis hydrogel effectively recruited and expanded conventional type 1 dendritic cells (cDC1s), significantly enhancing their capacity for antigen presentation of radiotherapy-released tumor antigens. Concurrently, the continuous delivery of OX40L promoted the robust activation and proliferation of tumor-infiltrating effector T cells. This dual-action mechanism initiated a potent antigen-specific immune response, leading to improved tumor eradication. The combined therapy of RH-FOLactis significantly enhanced the anti-tumor immune response and successfully transformed the immunosuppressive tumor microenvironment in pancreatic cancer from an immunologically "cold" state to a "hot" one, indicating a profound shift in immune cell infiltration and activity. This synergy was crucial for overcoming the inherent resistance of pancreatic tumors to immunotherapy. > The combined therapy of RH-FOLactis significantly enhanced the anti-tumor immune response and successfully transformed the immunosuppressive tumor microenvironment in pancreatic cancer from "cold" to "hot".