PD-L1 siRNA incorporation into a cationic liposomal tumor mRNA vaccine enhances cytotoxic T cell activation and prevents immune evasion

Engaging antigen-presenting cells and T lymphocytes is essential for invigorating the immune system's response to cancer. Nonetheless, challenges such as the low immunogenicity of tumor antigens, the genetic heterogeneity of tumor cells, and the elevated expression of immune checkpoint molecules frequently result in resistance to immunotherapy or enable immune evasion by tumors. To overcome this resistance, we developed a therapeutic tumor vaccine employing cationic liposomes to encapsulate MC38 total RNA alongside PD-L1 siRNA (siPD-L1). The encapsulated total RNA, enriched with tumor mRNA, effectively transduces dendritic cells (DCs), thereby enhancing antigen presentation. The incorporation of siPD-L1 specifically targets and diminishes PD-L1 expression on both DCs and tumor cells, synergistically amplifying the cytotoxic capabilities of CD8⁺ T cells. Furthermore, cationic liposomes play dual roles as carriers crucial for preserving the integrity of nucleic acids for antigen translation and as inhibitors of autophagy-a process essential for both promoting antigen cross-presentation and revitalizing MHC-I expression on tumor cells, thereby increasing their immunogenicity. This cationic liposomal vaccine represents a promising strategy in cancer immunotherapy, launching a multidimensional offensive against tumor cells that enhances cytotoxic T lymphocyte (CTL) activation and prevents tumor immune evasion.