Radiotherapy-synergized in situ hydrogel vaccine with engineered Lactococcus lactis FOLactis potentiates anti-tumor immunity in pancreatic cancer.

BACKGROUND

Immunotherapy has emerged as a promising strategy for pancreatic cancer. Radiotherapy not only mediates direct tumor cell killing but also provides a source of tumor antigens for dendritic cells (DCs) uptake and presentation via the induction of immunogenic cell death (ICD). However, the limited antigen presentation efficiency following radiotherapy and the rapid enzymatic degradation of adjuvants within the tumor microenvironment hinder the subsequent efficacy of immunotherapy.

METHODS

We developed an in situ hydrogel vaccine, Gel-FOLactis. Combined with 8Gy radiotherapy for treatment. This in situ vaccine employs a thermosensitive P407 hydrogel to encapsulate engineered Lactococcus lactis (FOLactis), enabling sustained intratumoral delivery of the immune-stimulating cytokines Fms-like tyrosine kinase 3 ligand (Flt3L) and co-stimulator OX40 ligand (OX40L).

RESULTS

The sustained release of Flt3L recruits and expands conventional type 1 dendritic cells, enhancing their antigen presentation capability for radiotherapy-released antigens. Concurrently, OX40L promotes the activation of tumor-infiltrating effector T cells. This synergy efficiently initiates a potent antigen-specific immune response, leading to improved tumor eradication.

CONCLUSIONS

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". These findings highlight the potential of RH-FOLactis as a novel and effective treatment strategy.