Abstract
The functional integrity of CD8+ T cells is tightly coupled to metabolic reprogramming, but how oxidative stress directs CD8+ T cell metabolic fitness in the tumor microenvironment (TME) remains elusive. Here, we report that SUMO-specific protease 7 (SENP7) senses oxidative stress to maintain the CD8+ T cell metabolic state and antitumor functions. SENP7-deficient CD8+ T cells exhibited decreased glycolysis and oxidative phosphorylation, resulting in attenuated proliferation in vitro and dampened antitumor functions in vivo. Mechanistically, CD8+ T cell–derived ROS triggered cytosolic SENP7–mediated PTEN deSUMOylation, thereby promoting PTEN degradation and preventing PTEN-dependent metabolic defects. Importantly, lowering T cell–intrinsic ROS restricted SENP7 cytosolic translocation and repressed CD8+ T cell metabolic and functional activity in human colorectal cancer samples. Our findings reveal that SENP7, as an oxidative stress sensor, sustains CD8+ T cell metabolic fitness and effector functions and unveil an oxidative stress–sensing machinery in tumor-infiltrating CD8+ T cells.
Highlights
CD8+ T cells mediate potent antitumor functions and play a critical role in immunotherapy-induced immune responses against cancer [1,2,3]
Since CD8+ T cells play a crucial role in cellmediated tumor killing [34], we inoculated WT and KO mice with MC38 murine colon cancer cells to determine whether SENP7 is required for antitumor T cell immune responses in vivo
To further confirm the CD8+ T cell-specific role of SENP7 in antitumor function, we adoptively transferred OT-I cells isolated from Senp7fl/flCd4-Cre OT-I (KO OT-I) mice and their WT OT-I littermates into WT mice bearing chicken ovalbumin-expressing MC38 (MC38-OVA) tumors
Summary
CD8+ T cells mediate potent antitumor functions and play a critical role in immunotherapy-induced immune responses against cancer [1,2,3]. Functionality and metabolic fitness are central determinants of CD8+ T cell efficacy in cancer immunotherapy [4]. The functional integrity of CD8+ T cells is tightly coupled to metabolic reprogramming [5,6,7]. Proliferating CD8+ T cells utilize aerobic glycolysis to support the rapid production of ATP and engage mitochondrial metabolism to generate sufficient amounts of bioenergetic intermediates and fulfill bioenergetic and biosynthetic demands [4, 8, 9]. The mechanism by which CD8+ T cell metabolic and functional activity is metabolically regulated in the TME remains unclear
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
