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CD8+ T cell activation leads to the rapid proliferation and differentiation of effector T cells (Teffs), which mediate antitumor immunity. Although aerobic glycolysis is preferentially activated in CD8+ Teffs, the mechanisms that regulate CD8+ T cell glucose uptake in the low-glucose and acidic tumor microenvironment (TME) remain poorly understood. Here, we report that the abundance of the glucose transporter GLUT10 is increased during CD8+ T cell activation and antitumor immunity. Specifically, GLUT10 deficiency inhibited glucose uptake, glycolysis, and antitumor efficiency of tumor-infiltrating CD8+ T cells. Supplementation with glucose alone was insufficient to rescue the antitumor function and glucose uptake of CD8+ T cells in the TME. By analyzing tumor environmental metabolites, we found that high concentrations of lactic acid reduced the glucose uptake, activation, and antitumor effects of CD8+ T cells by directly binding to GLUT10's intracellular motif. Disrupting the interaction of lactic acid and GLUT10 by the mimic peptide PG10.3 facilitated CD8+ T cell glucose utilization, proliferation, and antitumor functions. The combination of PG10.3 and GLUT1 inhibition or anti–programmed cell death 1 antibody treatment showed synergistic antitumor effects. Together, our data indicate that GLUT10 is selectively required for glucose uptake of CD8+ T cells and identify that TME accumulated lactic acid inhibits CD8+ T cell effector function by directly binding to GLUT10 and reducing its glucose transport capacity. Last, our study suggests disrupting lactate-GLUT10 binding as a promising therapeutic strategy to enhance CD8+ T cell–mediated antitumor effects. Editor's summary: CD8+ T cells are a critical part of antitumor immunity and depend on metabolites including glucose to maintain their function. Here, Liu et al. have evaluated targeting glucose transport 10 (GLUT10) as a way to increase CD8+ T cell function by disrupting the competitive binding of lactic acid that increased glucose uptake, thereby increasing proliferation and antitumor capacity. Authors developed a mimic peptide, PG10.3, to treat mouse models alone or in combination with anti–programmed cell death 1 to improve antitumor effects. This represents a new potential therapeutic option to improve outcomes for patients undergoing immunotherapy that will require further study. —Dorothy Hallberg [ABSTRACT FROM AUTHOR]

The dibromomaleimide derivative, N-(4-bromobutyl)-dibromomaleimide (dBMIB), is found to be a highly efficient coupling agent to dimerize thiol-terminated hydrophilic polymers by substituent reaction. When mono-thiol poly(ethylene oxide) (PEO45-SH) is mixed with dBMIB in an equivalent molar feed in water, a dimer of PEO45 with a maleimide unit located at the chain center, (PEO45)2MIB, is obtained quantitatively. The dBMIB is also used to dimerize thiol- terminated poly( N-(2-acryloyloxyethyl) pyrrolidone) and poly( N, N-dimethyl acrylamide). Moreover, the butylene bromide of (PEO45)2MIB is transferred into a butylene azide, which is allowed to react with alkynyl-terminated polystyrene to give a A2B miktoarm star polymer via a copper-catalyzed azide-alkyne cycloaddition coupling reaction. [ABSTRACT FROM AUTHOR]

CD8 + T cell activation leads to the rapid proliferation and differentiation of effector T cells (T effs ), which mediate antitumor immunity. Although aerobic glycolysis is preferentially activated in CD8 + T effs , the mechanisms that regulate CD8 + T cell glucose uptake in the low-glucose and acidic tumor microenvironment (TME) remain poorly understood. Here, we report that the abundance of the glucose transporter GLUT10 is increased during CD8 + T cell activation and antitumor immunity. Specifically, GLUT10 deficiency inhibited glucose uptake, glycolysis, and antitumor efficiency of tumor-infiltrating CD8 + T cells. Supplementation with glucose alone was insufficient to rescue the antitumor function and glucose uptake of CD8 + T cells in the TME. By analyzing tumor environmental metabolites, we found that high concentrations of lactic acid reduced the glucose uptake, activation, and antitumor effects of CD8 + T cells by directly binding to GLUT10's intracellular motif. Disrupting the interaction of lactic acid and GLUT10 by the mimic peptide PG10.3 facilitated CD8 + T cell glucose utilization, proliferation, and antitumor functions. The combination of PG10.3 and GLUT1 inhibition or anti-programmed cell death 1 antibody treatment showed synergistic antitumor effects. Together, our data indicate that GLUT10 is selectively required for glucose uptake of CD8 + T cells and identify that TME accumulated lactic acid inhibits CD8 + T cell effector function by directly binding to GLUT10 and reducing its glucose transport capacity. Last, our study suggests disrupting lactate-GLUT10 binding as a promising therapeutic strategy to enhance CD8 + T cell-mediated antitumor effects.