Reprogramming Postablation Tumor Immune Microenvironment with Dual-Function Nanotherapeutic Immunomodulator for...

Radiofrequency ablation (RFA) has emerged as a predominant minimally invasive approach for liver tumors, achieving favorable therapeutic outcomes and triggering a systemic immune response via the release of tumor-associated antigens. However, postablation tumor recurrence remains a critical challenge in clinics. Our previous studies revealed that ablation-induced immunosuppression, primarily characterized by the expansion and activation of myeloid-derived suppressor cells (MDSCs), critically compromised the host's antitumor immunity, impeding residual tumor eradication and fostering a permissive niche for recurrence. To decisively address this fundamental limitation and harness the potential of ablation to stimulate antitumor immunity, we proposed a nanotherapeutic immunomodulatory strategy that synchronously reversed postablation MDSC-driven immunosuppression ("release the immunosuppressive brakes") while activating the stimulator of interferon gene (STING) pathway-mediated antitumor immune priming ("apply the immunostimulatory accelerator") in the systemic immune landscape. Through rational design, we engineered the nanotherapeutic immunomodulators (termed cA@NPs, where NPs are nanoparticles) coencapsulating the STING agonist 2',3'-cyclic guanosine adenosine monophosphate (cGAMP) and the MDSC-differentiating agent all-trans retinoic acid (ATRA), effectively overcoming their disparate pharmacokinetic profiles while ensuring spatiotemporally coordinated delivery. The residual tumor models provided definitive evidence that reversing postablation MDSC-driven immunosuppression was essential for achieving more effective antitumor immunity. Comprehensive preclinical evaluations further demonstrated the cA@NPs' robust capacity to suppress micrometastasis, distant tumors, and orthotopic lesions via multidimensional remodeling of the postablation immune landscape. These findings established a mechanistic foundation for the clinical translation of ablation-synergized nanotherapy, effectively bridging localized thermal intervention with systemic immune potentiation to address tumor recurrence.