Obesity contributes to about 30% incidence of colorectal cancer (CRC). Obese tumor microenvironment compromises anti-tumor immunity by eliciting exhausted T cells (Tex). Hypothesizing that Dahuang Fuzi Baijiang Decoction (DFB), a combined classical prescription from "Synopsis of Golden Chamber", modulates the differentiation of tumor-infiltrating CD8+ T cells, we firstly demonstrate that DFB regresses tumor growth in high-fat diet induced obese mice via expanding PD-1int TIM3- and restricting PD-1hi TIM3+ subset. TCF1 is highly expressed in PD-1int TIM3- subset but is absent in PD-1hi TIM3+ cells. We next confirm that progenitor PD-1int TCF+ cells robustly produce TNFɑ and IFNγ while terminally differentiated PD-1int TCF+ cells have defects in generating TNFɑ. With transgenic ob/ob mice, we find that DFB produces cooperative efficacy with anti-PD-1 (ɑPD-1) by limiting PD-1hi Tim3+ subset and amplifying PD-1int TCF+ population. Finally, we define CCR2+ CD8+ subset as teminal Tex and identify that the differentiation from progenitor to terminal Tex is driven, at least in part, by CCL2/CCR2 axis. CCR2 inhibitor enhances the response to ɑPD-1 by promoting the counts of progenitor Tex. Altogether, DFB dampens CCL2 and preserves progenitor Tex in obese microenvironment to restrain CRC progression. These finds provide unambiguous evidence that traditional Chinese formula DFB can prevent tumor progression by modulating adaptive immunity and give rise to strong rationale for further clinical verification.This article is protected by copyright. All rights reserved.