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<p>The clinical efficacy of immunotherapy in advanced esophageal squamous cell carcinoma (ESCC) remains suboptimal, as most patients eventually develop drug resistance and experience disease progression. Here, we identify Collagen Triple Helix Repeat Containing 1 (CTHRC1) as a critical mediator of immunotherapy resistance in ESCC. Elevated CTHRC1 expression was observed in tumors unresponsive to immune checkpoint blockade and was associated with enhanced platelet activity and infiltration of megakaryocytes (MKs) into the tumor microenvironment. Mechanistically, CTHRC1 facilitated MK activation and recruitment, fostering an immunosuppressive niche that impaired cytotoxic T-cell activity and promoted cell exhaustion. To therapeutically target this axis, we developed a lipid nanoparticle (LNP)-encapsulated mRNA vaccine encoding CTHRC1. In preclinical ESCC models, the CTHRC1-mRNA-LNP vaccine elicited robust antitumor immunity. Notably, the combination of CTHRC1-mRNA vaccination with anti–PD-1 therapy induced synergistic intratumoral T-cell infiltration, depletion of MKs, reversal of immunosuppression, and durable tumor regression. Collectively, these findings uncover an unrecognized immunoregulatory function of CTHRC1 in ESCC and highlight its therapeutic targeting as a promising strategy to enhance the efficacy of immune checkpoint blockade.</p> Graphical abstract <p>CTHRC1 directly engages integrin αIIbβ3 and to drive megakaryocyte and activates the TLR4–NF-κB-IL-8 axis to promote megakaryocyte/platelet infiltration, promoting an immunosuppressive ESCC TME and T-cell dysfunction. Administration of a CTHRC1 mRNA–LNP vaccine elicits potent antigen-specific humoral and cellular immunity, dismantles megakaryocyte-mediated immune exclusion, converts a cold TME into an inflamed state, and restores sensitivity to PD-1 blockade.</p> <p></p>

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CTHRC1 drives megakaryocyte-mediated immunotherapy resistance in esophageal squamous cell carcinoma via the integrin αIIbβ3/Rap1 pathway and is targetable by mRNA vaccination

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月21日

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  • Yixin Liu,
  • Jianfeng Zhou,
  • Mengyuan Song,
  • Jian Wang,
  • Qixin Shang,
  • Jiajia Du,
  • Yanxin Li,
  • Xiangzheng Chen,
  • Jing Wang,
  • Xuerui Liao,
  • Longqi Chen,
  • Weimin Li,
  • Yong Yuan,
  • Yushang Yang,
  • Yangping Wu

摘要

The clinical efficacy of immunotherapy in advanced esophageal squamous cell carcinoma (ESCC) remains suboptimal, as most patients eventually develop drug resistance and experience disease progression. Here, we identify Collagen Triple Helix Repeat Containing 1 (CTHRC1) as a critical mediator of immunotherapy resistance in ESCC. Elevated CTHRC1 expression was observed in tumors unresponsive to immune checkpoint blockade and was associated with enhanced platelet activity and infiltration of megakaryocytes (MKs) into the tumor microenvironment. Mechanistically, CTHRC1 facilitated MK activation and recruitment, fostering an immunosuppressive niche that impaired cytotoxic T-cell activity and promoted cell exhaustion. To therapeutically target this axis, we developed a lipid nanoparticle (LNP)-encapsulated mRNA vaccine encoding CTHRC1. In preclinical ESCC models, the CTHRC1-mRNA-LNP vaccine elicited robust antitumor immunity. Notably, the combination of CTHRC1-mRNA vaccination with anti–PD-1 therapy induced synergistic intratumoral T-cell infiltration, depletion of MKs, reversal of immunosuppression, and durable tumor regression. Collectively, these findings uncover an unrecognized immunoregulatory function of CTHRC1 in ESCC and highlight its therapeutic targeting as a promising strategy to enhance the efficacy of immune checkpoint blockade.

Graphical abstract

CTHRC1 directly engages integrin αIIbβ3 and to drive megakaryocyte and activates the TLR4–NF-κB-IL-8 axis to promote megakaryocyte/platelet infiltration, promoting an immunosuppressive ESCC TME and T-cell dysfunction. Administration of a CTHRC1 mRNA–LNP vaccine elicits potent antigen-specific humoral and cellular immunity, dismantles megakaryocyte-mediated immune exclusion, converts a cold TME into an inflamed state, and restores sensitivity to PD-1 blockade.