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<p>Fibrotic colorectal cancers (CRC) are largely microsatellite-stable and display desmoplastic stroma with poor immune infiltration. Here we identify thrombospondin-2 (THBS2) as a key regulator of the immune-exclusionary phenotype in fibrotic CRC. THBS2 is highly expressed by matrix cancer-associated fibroblasts at the tumor front. In an orthotopic model using desmoplastic tumor organoids, global or fibroblast-specific Thbs2 deletion disrupts the exclusionary barrier and increases intratumoral CD8 T cells. Mechanistically, THBS2 limits recruitment of CXCR3<sup>+</sup> CD8 T cells by restraining dendritic- and macrophage-derived CXCL9/10. Depletion of these myeloid cells or blockade of CXCL9/10-CXCR3 signaling abolishes the enhanced CD8 T-cell influx and antitumor efficacy. Spatial profiling demonstrates that THBS2 loss induces proximity between CD8 T cells and myeloid cells and upregulates chemokines. Despite increased infiltration, CD8 T cells manifest exhaustion, rendering tumors highly susceptible to immune checkpoint blockade. THBS2 thus represents a tractable CAF-restricted target to overcome immune exclusion in fibrotic CRCs.</p>

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Targeting fibroblast derived thrombospondin 2 disrupts an immune-exclusionary environment at the tumor front in colorectal cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月23日

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  • Kosuke Iwane,
  • Yuki Nakanishi,
  • Yu Muta,
  • Jiayu Chen,
  • Kento Yasumura,
  • Mayuki Omatsu,
  • Naoki Aoyama,
  • Munehiro Ikeda,
  • Yoko Masui,
  • Liyang Cai,
  • Go Yamakawa,
  • Kensuke Hamada,
  • Kenta Mizukoshi,
  • Munenori Kawai,
  • Kei Iimori,
  • Shinnosuke Nakayama,
  • Nobukazu Agatsuma,
  • Takahiro Utsumi,
  • Munemasa Nagao,
  • Takahisa Maruno,
  • Yukiko Hiramatsu,
  • Nobuyuki Kakiuchi,
  • Masahiro M. Nakagawa,
  • Yasuhiro Fukui,
  • Yukina Kusunoki,
  • Hiroaki Kasashima,
  • Masakazu Fujimoto,
  • Yoshiro Itatani,
  • Toshiaki Kogame,
  • Akihisa Fukuda,
  • Masakazu Yashiro,
  • Kiyoshi Maeda,
  • Kenji Kabashima,
  • Kazutaka Obama,
  • Seishi Ogawa,
  • Maria T. Diaz-Meco,
  • Jorge Moscat,
  • Hiroshi Seno

摘要

Fibrotic colorectal cancers (CRC) are largely microsatellite-stable and display desmoplastic stroma with poor immune infiltration. Here we identify thrombospondin-2 (THBS2) as a key regulator of the immune-exclusionary phenotype in fibrotic CRC. THBS2 is highly expressed by matrix cancer-associated fibroblasts at the tumor front. In an orthotopic model using desmoplastic tumor organoids, global or fibroblast-specific Thbs2 deletion disrupts the exclusionary barrier and increases intratumoral CD8 T cells. Mechanistically, THBS2 limits recruitment of CXCR3+ CD8 T cells by restraining dendritic- and macrophage-derived CXCL9/10. Depletion of these myeloid cells or blockade of CXCL9/10-CXCR3 signaling abolishes the enhanced CD8 T-cell influx and antitumor efficacy. Spatial profiling demonstrates that THBS2 loss induces proximity between CD8 T cells and myeloid cells and upregulates chemokines. Despite increased infiltration, CD8 T cells manifest exhaustion, rendering tumors highly susceptible to immune checkpoint blockade. THBS2 thus represents a tractable CAF-restricted target to overcome immune exclusion in fibrotic CRCs.