Current
immune checkpoint blockade (ICB) immunotherapeutics have revolutionized
cancer treatment. However, many
cancers especially the "immunologically cold"
tumors, do not respond to ICB, prompting the search for additional strategies to achieve durable responses. The cGAS-
STING pathway, as an essential immune response pathway, has been demonstrated for a potent target to sensitize ICB
immunotherapy. However, the low efficiency of conventional
STING agonists limits their clinical application. Recent studies have shown that
DNA topoisomerase I (TOPI) inhibitor chemodrug SN38 can activate the cGAS-
STING pathway and induce an immune response through DNA damage, while the traditional
statins medication
lovastatin was found to inhibit DNA damage repair, which may in turn upregulate the damaged
DNA level. Herein, we have developed a liposomal carrier co-loaded with SN38 and
lovastatin (SL@Lip), which can be accumulated in
tumors and efficiently released SN38 and
lovastatin, addressing the problem of weak solubility of these two drugs. Importantly,
lovastatin can increase DNA damage and enhance the activation of cGAS-
STING pathway, coordinating with SN38
chemotherapy and exhibiting the enhanced combinational
immunotherapy of PD-1 antibody by remodeling the tumor microenvironment in mouse
colorectal cancer of both subcutaneous and orthotopic xenograft models. Overall, this study demonstrates that
lovastatin-assisted cGAS-
STING stimulation mediated by liposomal delivery system significantly strengthened both
chemotherapy and
immunotherapy of
colorectal cancer, providing a clinically translational strategy for combinational ICB
therapy in the "immunologically cold"
tumors.