Blocking LIF and PD-L1 enhances the antitumor efficacy of SBRT in murine PDAC models

We showed that simultaneous inhibition of LIF and PD-L1 significantly amplified the antitumor efficacy of SBRT, resulting in extended survival. The triple therapy (SBRT+anti-LIF+anti-PD-L1) generated an immunostimulatory tumor microenvironment, characterized by a proinflammatory shift in the cytokine/chemokine profile, increased infiltration of effector CD8⁺ T cells, and upregulated activation or maturation signals in tumor-infiltrating CD8⁺ T cells and macrophages. The beneficial effects of triple therapy were mostly abrogated by depletion of CD8⁺ T cells. In addition, triple therapy downregulated pathways related to tumor stemness, proliferation, and metabolism, and reduced EMT. Importantly, the combination of local SBRT treatment with systemic LIF and PD-L1 blockade resulted in long-term systemic antitumor memory.