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<p>The immune-excluded tumor immune microenvironment (TIME) limits responses to ICIs. Cancer-associated fibroblasts are the most abundant stromal population and key regulators of immune suppression; however, the upstream cues that program pathogenic CAF states and the mechanisms of the immune-excluded TIME remain poorly defined. Here, by combining single-cell RNA sequencing and functional validation, we report that tumor cell-released autophagosome (TRAP) programs inflammatory CAFs (iCAFs) and triggers cathepsin L-dependent intracellular cleavage of C3 into C3a via the HSP70–TLR4–MyD88–ERK/p38 pathway. iCAF-derived C3a affects C3a on TAMs, promotes TAM accumulation in the iCAF-rich stroma, limits TIL trafficking into tumor nests, and reinforces an immune-excluded TIME. Disrupting the TRAP–iCAF–C3a/C3aR axis remodels the immune-excluded TIME and sensitizes tumors to anti-PD-L1 therapy. In clinical cohorts, plasma TRAP and C3a levels increased with disease stage, and their combination improved the discrimination of patients with breast cancer from controls (AUC = 0.96). These data define a TRAP-driven stromal–immune circuit that promotes immune exclusion and suggest that the C3a–C3aR axis is a potential target for enhancing ICI efficacy.</p>

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Tumor cell-released autophagosome (TRAP) programs inflammatory CAFs to drive the immune-excluded TIME through C3a

  • 期刊论文

  • 发表日期：

    2026年7月29日

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  • Xuru Wang,
  • Yiting Wei,
  • Chengdong Wu,
  • Xiaohe Zhou,
  • Xiaotong Sun,
  • Xiaoyue Du,
  • Jinpeng Chen,
  • Jing Chen,
  • Wenqi Zhang,
  • Xiangwei Bo,
  • Yunpeng Zhang,
  • Bo Shen,
  • Shaodi Wen,
  • Lixin Wang

摘要

The immune-excluded tumor immune microenvironment (TIME) limits responses to ICIs. Cancer-associated fibroblasts are the most abundant stromal population and key regulators of immune suppression; however, the upstream cues that program pathogenic CAF states and the mechanisms of the immune-excluded TIME remain poorly defined. Here, by combining single-cell RNA sequencing and functional validation, we report that tumor cell-released autophagosome (TRAP) programs inflammatory CAFs (iCAFs) and triggers cathepsin L-dependent intracellular cleavage of C3 into C3a via the HSP70–TLR4–MyD88–ERK/p38 pathway. iCAF-derived C3a affects C3a on TAMs, promotes TAM accumulation in the iCAF-rich stroma, limits TIL trafficking into tumor nests, and reinforces an immune-excluded TIME. Disrupting the TRAP–iCAF–C3a/C3aR axis remodels the immune-excluded TIME and sensitizes tumors to anti-PD-L1 therapy. In clinical cohorts, plasma TRAP and C3a levels increased with disease stage, and their combination improved the discrimination of patients with breast cancer from controls (AUC = 0.96). These data define a TRAP-driven stromal–immune circuit that promotes immune exclusion and suggest that the C3a–C3aR axis is a potential target for enhancing ICI efficacy.