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The obese tumor microenvironment compromises antitumor immunity by eliciting exhausted T cells (Tex). Hypothesizing that Dahuang Fuzi Baijiang decoction (DFB) is a combined classical prescription from the \u201cSynopsis of Prescriptions of the Golden Chamber\u201d. We first determined that DFB regresses tumor growth in high\u2010fat diet\u2013induced obese mice by expanding the TIM3<jats:sup>\u2212<\/jats:sup> subset with intermediate expression of programmed cell death\u20101 (PD\u20101<jats:sup>int<\/jats:sup>TIM<jats:sup>3\u2212<\/jats:sup>) and restricting the PD\u20101<jats:sup>hi<\/jats:sup>TIM3<jats:sup>+<\/jats:sup> subset. Transcription factor 1 (TCF1) is highly expressed in the PD\u20101<jats:sup>int<\/jats:sup>TIM3<jats:sup>\u2212<\/jats:sup> subset but is absent in PD\u20101<jats:sup>hi<\/jats:sup>TIM3<jats:sup>+<\/jats:sup> cells. We next confirmed that progenitor PD\u20101<jats:sup>int<\/jats:sup>TCF<jats:sup>+<\/jats:sup> cells robustly produce tumor necrosis factor\u2010\u03b1 (TNF\u03b1) and interferon\u2010\u03b3, whereas terminally differentiated PD\u20101<jats:sup>int<\/jats:sup>TCF<jats:sup>+<\/jats:sup> cells have defects in generating TNF\u03b1. With transgenic <jats:italic>ob<\/jats:italic>\/<jats:italic>ob<\/jats:italic> mice, we found that DFB produces cooperative efficacy with anti\u2010PD\u20101 (\u03b1PD\u20101) by limiting the PD\u20101<jats:sup>hi<\/jats:sup>Tim3<jats:sup>+<\/jats:sup> subset and amplifying the PD\u20101<jats:sup>int<\/jats:sup>TCF<jats:sup>+<\/jats:sup> population. Finally, we defined the recombinant chemokine C\u2010C\u2010motif receptor 2 (CCR2)<jats:sup>+<\/jats:sup>CD8<jats:sup>+<\/jats:sup> subset as terminal Tex and identified that the differentiation from progenitor to terminal Tex is driven, at least in part, by the chemokine (C\u2010C motif) ligand 2 (CCL2)\/CCR2 axis. The CCR2 inhibitor enhances the response to \u03b1PD\u20101 by promoting the counts of progenitor Tex. Altogether, DFB dampens CCL2 and preserves progenitor Tex in the obese microenvironment to restrain CRC progression. These findings provide unambiguous evidence that the traditional Chinese formula DFB can prevent tumor progression by modulating adaptive immunity and establish a strong rationale for further clinical verification.<\/jats:p>","DOI":"10.1111\/cas.15311","type":"journal-article","created":{"date-parts":[[2022,3,3]],"date-time":"2022-03-03T02:27:35Z","timestamp":1646274455000},"page":"1739-1751","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Dahuang Fuzi Baijiang decoction restricts progenitor to terminally exhausted T cell differentiation in colorectal cancer"],"prefix":"10.1111","volume":"113","author":[{"given":"Yihua","family":"Xu","sequence":"first","affiliation":[{"name":"The Key Laboratory of Molecular Biology State Administration of Traditional Chinese Medicine School of Traditional Chinese Medicine Southern Medical University  Guangzhou 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