CELL INTELLIGENCE · 肿瘤细胞治疗研究

Radiofrequency ablation (RFA) remains one of the effective therapeutic modalities for treatment of hepatocellular carcinoma (HCC). However, incomplete RFA (iRFA) frequently creates an immunosuppressive microenvironment (ISME) in tumors, which markedly jeopardizes therapeutic benefits. To overcome this therapeutic hurdle, we designed a completely new ZIF-8-NH 2 -based nanoplatform (NP) that contained a CpG oligodeoxynucleotide, clonidine (CLD), and an α 2 -adrenergic receptor agonist. The ZIF-8-NH 2 -based NP exhibited high drug-loading capacity, sustained release and intratumoral retention. Intratumoral delivery of ZIF-8-NH 2 -based NP into HCC tumors resulted in polarization of M2-tumor-associated macrophages (M2-TAMs) to become M1-TAMs that markedly increased C-X-C motif chemokine 10 (CXCL10) production. M1-TAM-derived CXCL10 enhanced tumor recruitment of CD8 + T cells and NK cells, which collectively executed antitumor effects. Through this mechanism, we showed that ZIF-8-NH 2 -based NP sensitized the therapeutic effect of an anti-PD-L1 blockade for HCC treatment. Based on these findings, we propose a new therapeutic paradigm of a triple combination of ZIF-8-NH 2 -based NP plus immune checkpoint inhibitors (ICIs) plus iRFA. In a clinically relevant mouse HCC model, we validated this new therapeutic concept as an effective approach for treatment of HCC. Together, these data pave a new therapeutic avenue for effective treatment of HCC and likely other types of cancer.