Reversing cisplatin-induced immunosuppression with a selenium-integrated nanoliposome to synergize natural killer cell chemoimmunotherapy for cervical cancer

Cisplatin (CDDP)-based chemotherapy remains the cornerstone of cervical cancer treatment; however, its efficacy is severely compromised by an inherent therapeutic paradox where CDDP induces a systemic downregulation of selenoproteins in natural killer (NK) cells, driving them toward a senescent state that nullifies the potential of chemoimmunotherapy. Here, an optimized lipid nanoparticle codelivering CDDP and ultrasmall selenium nanoparticles (CDDP/UsSe@LNP) was developed to resolve this conflict. This nanoplatform exhibited excellent pharmaceutical properties including high drug loading and pH-responsive release, leading to reduced systemic toxicity and enhanced tumor cytotoxicity. Furthermore, the integrated selenium not only shielded NK92 cells from CDDP-induced damage but also reprogrammed tumor cells to become susceptible to NK cell attack. This dual-action mechanism was achieved by augmenting NK cell-activating receptors and cytotoxic granule release while reversing the immunosuppressive cytokine milieu. In this study, a novel chemoimmunotherapeutic paradigm for cervical cancer that integrates nanocarrier-optimized chemotherapy with adoptive NK cell therapy was established.