Fig. 7: Inhibition of the endogenous lactate production of CAFs alleviates the immunosuppression in MPE.

a, b Lactate (a) and CXCL16 (b) levels measured in MPE from mice treated with LDHA^−/− 3T3 fibroblasts or control fibroblasts. c–j Flow cytometry plots (c, e, g and i) and comparisons (d, f, h and j) of the frequencies of TNFR2⁺ T_reg cells (c and d), IFN-γ⁺CD8⁺ T cells (e and f), granzyme B⁺CD8⁺ T cells (g and h) and perforin⁺CD8⁺ T cells (i and j) in MPE. k Schematic diagram illustrating the proposed mechanism: CAFs in MPE undergo glycolysis, leading to elevated endogenous lactate levels. This increase in lactate induces H3K18 lactylation modification at the promoter regions of both the CXCL16 gene and its transcription factor FOXO3, thereby promoting CXCL16 expression. TNFR2⁺ T_reg cells, which express high levels of CXCR6, the only known receptor for CXCL16, are efficiently recruited into MPE. This recruitment dampens the antitumor response generated by CD8⁺ T cells, leading to the immunosuppression and progression of MPE (by Figdraw). Data shown in a–j are representative of at least three independent experiments (mean ± s.d.). Statistical analysis was performed using unpaired two-tailed Student’s t-test (a and b) and one-way ANOVA (d, f, h and j). **P < 0.01, ***P < 0.001, ****P < 0.0001. ns not significant.