Regulating the Obesity-Related Tumor Microenvironment to Improve Cancer Immunotherapy

Abstract

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/p DNA (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.

Clinical variables associated with immune checkpoint inhibitor outcomes in patients with metastatic urothelial carcinoma: a multicentre retrospective cohort study

“…Some studies have reported that obesity is associated with improved survival in some, but not all, patients with cancer, which is referred to the ‘obesity paradox’ 40. Numerous studies have shown that obesity can cause immune cell dysfunction,41–44 while others argue that the chronic low-grade inflammation underpinning obesity creates a proinflammatory state that synergises with immunotherapy 45 46…”

Clinical variables associated with immune checkpoint inhibitor outcomes in patients with metastatic urothelial carcinoma

“…Some studies have reported that obesity is associated with improved survival in some, but not all, patients with cancer, which is referred to the "obesity paradox" [41]. Numerous studies have shown that obesity can cause immune cell dysfunction [42][43][44][45], while others argue that the chronic lowgrade inflammation underpinning obesity creates a pro-inflammatory state that synergizes with immunotherapy [46,47].…”

Developing a machine learning-based prognosis and immunotherapeutic response signature in colorectal cancer: insights from ferroptosis, fatty acid dynamics, and the tumor microenvironment

“…This process has garnered significant attention as a potential target for cancer therapy, particularly because it is associated with regulatory and CD8+ T cells ( 11 – 13 ). Glutathione peroxidase 4 (GPx4) and prolyl hydroxylase-3 (PHD3) represent significant regulators of ferroptosis and fatty acid metabolism, respectively, emphasizing the potential role of both in immunotherapy ( 14 , 15 ). Recent studies indicated a significant association between fatty acid metabolism and ferroptosis.…”