Reprogramming Metabolism and Immunity: Nanotechnology’s Promise for Hepatocellular Carcinoma Precision Therapy

Mingrong Cheng,1,* Yucheng Ni,1,* Wei Zhang,1,* Qinghua Wu1,2 1Department of General Surgery, Nanxiang Branch of Ruijin Hospital, Shanghai, 201802, People’s Republic of China; 2Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Mingrong Cheng, Department of General Surgery, Nanxiang Branch of Ruijin Hospital, No. 495 Zhongren Road, Nanxiang Town, Jiading District, Shanghai, 201802, People’s Republic of China, Email [email protected] Qinghua Wu, Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, No. 999, Hope Road, Jiading District, Shanghai, 200032, People’s Republic of China, Email [email protected]: The treatment of hepatocellular carcinoma (HCC) faces multiple dilemmas, including limited applicability of local therapy, easy development of resistance to targeted drugs, and low response rate to immune checkpoint inhibitors (ICIs). The core crux lies in the “metabolic reprogramming-immune suppression” vicious cycle and tumor heterogeneity. This review aims to clarify the crosstalk between metabolic reprogramming and immune suppression in HCC, and summarize the design principles of nanoplatforms for synchronous intervention in metabolism and immunity. Nanotechnology, with core advantages of precise targeting, tumor microenvironment responsiveness, and multifunctional synergy, enables targeted regulation of glucose, fatty acid, and amino acid metabolic pathways. It synergizes with ICIs and local therapies to reshape the immunosuppressive microenvironment, and the “metabolic subtype-nanocarrier” matching strategy shows promising clinical potential. Current applications face challenges in carrier performance, personalized strategies, and clinical translation. Future development focusing on carrier optimization, multi-omics-based subtype matching, and standardized evaluation systems will promote nanotechnology to evolve from “broad-spectrum regulation” to “precise adaptation”, providing a core tool for overcoming HCC treatment bottlenecks and advancing precision therapy.Keywords: hepatocellular carcinoma, metabolic-immunomodulation, nanodelivery systems, combination therapy, tumor microenvironment, clinical translation