Loss of Lepr in Fibroblasts Drives Tumor Development by Promoting Macrophage Infiltration

ABSTRACT

Cancer‐associated fibroblasts (CAFs) are critical regulators of colorectal cancer (CRC) progression, yet the mechanisms governing their functional plasticity and state transitions remain incompletely understood. Here, we uncover a tumor‐driven fibroblast state transition in CRC characterized by loss of leptin receptor (Lepr) expression and acquisition of pro‐inflammatory features. We show that cooperative TNFα and TGFβ signaling drives this reprogramming, accompanied by repression of the Tcf21‐Lepr regulatory axis. Fibroblasts undergoing this transition acquire the capacity to promote macrophage recruitment and accelerate tumor development. Loss of Lepr or Tcf21 in fibroblasts upregulates Csf3, which contributes to the enhanced macrophage‐recruiting capacity of the reprogrammed fibroblasts. Consistently, blockade of TNFα and TGFβ signaling disrupts fibroblast reprogramming and attenuates macrophage infiltration. Together, our findings uncover how inflammatory signaling reshapes stromal cell states to promote macrophage accumulation, ultimately fostering a pro‐tumorigenic niche that accelerates CRC progression.