Bisphosphonate-Mineralized Nano-IFNγ Suppresses Residual Tumor Growth Caused by Incomplete Radiofrequency Ablation through Metabolically Remodeling Tumor-Associated Macrophages

Radiofrequency ablation (RFA), as a minimally invasive surgery strategy based on local thermal-killing effect, is widely used in the clinical treatment of multiple solid tumors. Nevertheless, RFA cannot achieve the complete elimination of tumor lesions with larger burden or proximity to blood vessels. Incomplete RFA (iRFA) has even been validated to promote residual tumor growth due to the suppressive tumor immune microenvironment (TIME). In this study, tumor-associated macrophages (TAMs) and their transformation from M1 to M2 type after iRFA are discovered as the key target and mechanism. A bisphosphonate (zoledronate)-mineralized nanoparticulated IFNγ (Nano-IFNγ/Zole) is then fabricated to eliminate the negative effect of iRFA by reprogramming TAMs. IFNγ is assembled into a nanostructure via the interaction with zoledronate and zinc/calcium ions. Nanoparticulated IFNγ concentrates in the tumor ablation site to play a long-term remodeling role. Zoledronate as an inhibitor of mevalonate metabolic pathway synergistically involves in the trans-differentiation of TAMs. Mechanistically, zoledronate reduces lysosomal acidification, enhances tumor antigen cross-presentation, and activates transcription factor TFEB by inhibiting isoprene modification of the Rab protein family. These mechanisms, in conjunction with IFNγ-activated JAK/STAT1 signaling, accelerate the reprogramming of TAMs from the M2 to M1 type, remodel the suppressive tumor immune microenvironment after iRFA. Considering that zoledronate and IFNγ in Nano-IFNγ/Zole have already been approved in clinics, this integrative nano-drug delivery system establishes an effective strategy with great translational promise to overcome the poor prognosis after clinically incomplete RFA.