题目：

Regulating the Obesity-Related Tumor Microenvironment to Improve Cancer Immunotherapy

作者：

Huapan Fang^1,3, Yicheng Wu¹, Linfu Chen¹, Zhiqin Cao¹, Zheng Deng¹, Rui Zhao¹, Lin Zhang¹, Yang Yang²*, Zhuang Liu¹*, and Qian Chen¹*

单位：

¹Institute of Functional Nano and Soft Materials, Jiangsu Key Laboratory for Carbon-Based Functional Materials and Devices, Soochow University, Suzhou 215123, China

²Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai 200433, China

³College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China

摘要：

Obesity usually induces systemic metabolic disturbances, including in the tumor microenvironment (TME). This is because adaptive metabolism related to obesity in the TME with a low level of prolyl hydroxylase-3 (PHD3) depletes the major fatty acid fuels of CD8⁺ T cells and leads to the poor infiltration and unsatisfactory function of CD8⁺ T cells. Herein, we discovered that obesity could aggravate the immunosuppressive TME and weaken CD8⁺ T cell-mediated tumor cell killing. We have thus developed gene therapy to relieve the obesity-related TME to promote cancer immunotherapy. An efficient gene carrier was prepared by modifying polyethylenimine with p-methylbenzenesulfonyl (abbreviated as PEI-Tos) together with hyaluronic acid (HA) shielding, achieving excellent gene transfection in tumors after intravenous administration. HA/PEI-Tos/pDNA (HPD) containing the plasmid encoding PHD3 (pPHD3) can effectively upregulate the expression of PHD3 in tumor tissues, revising the immunosuppressive TME and significantly increasing the infiltration of CD8⁺ T cells, thereby improving the responsiveness of immune checkpoint antibody-mediated immunotherapy. Efficient therapeutic efficacy was achieved using HPD together with αPD-1 in colorectal tumor and melanoma-bearing obese mice. This work provides an effective strategy to improve immunotherapy of tumors in obese mice, which may provide a useful reference for the immunotherapy of obesity-related cancer in the clinic.

影响因子：

18.027

分区情况：

一区

链接：

https://pubs.acs.org/doi/10.1021/acsnano.2c11159