Current immunotherapy has limited efficacy in hepatocellular carcinoma (HCC) due to the immunosuppressive tumor microenvironment (TME). The activation of the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS)-stimulator of the interferon genes (STING) pathway demonstrates great potential to unleash the immunosuppressive TME. The capacity of melarsoprol (MEL; an arsenic-containing drug) on activating the cGAS-STING pathway in HCC cells for antitumor immunotherapy was confirmed for the first time in this study. When MEL (particularly at high doses) activated the cGAS-STING pathway； however, HCC growth was not fully inhibited, mainly due to the hyperactivation of tumor necrosis factor α (TNF-α; a cytokine associated with the cGAS-STING pathway). Accordingly, lenalidomide (LEN; a clinically approved TNF-α inhibitor) was used to alleviate pro-tumorigenic effects of the MEL-activated cGAS-STING pathway while maintaining immunotherapeutic effects. To modulate the cGAS-STING pathway , a poly(D,L-lactic-co-glycolic acid) (PLGA) nanoparticle (NP) was used for co-delivery of MEL and LEN, and the co-loaded NP was coated with aminoethyl anisamide (AEAA, a ligand for Sigma-1 receptor)-modified erythrocyte membrane, forming a co-formulation. In this study, co-formulation was able to modulate the cGAS-STING-mediated efficacy and reverse the immunosuppressive TME in allograft and carcinogen-induced orthotopic HCC mouse models, respectively. Our study reveals an intrinsic hurdle to DNA damaging drug-mediated cGAS-STING monotherapy and provides a promising combination strategy to tackle immunosuppression in HCC.