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<p>Resistance to immune checkpoint blockade (ICB) therapy in certain solid tumors remains a major research focus; yet, the underlying mechanisms are not fully understood. Our previous studies demonstrated that subcutaneous tumors formed by a mixture of bone marrow-derived myofibroblasts (BMFs) and tumor cells not only grew faster than those formed by tumor cells alone but were also resistant to ICB therapy. However, the specific mechanism by which BMFs mediate this immune resistance remained unclear. In this study, we established a “BMF + MC38” mixed-cell subcutaneous tumor model to further validate its ICB therapy-resistant phenotype, investigate the mechanism underlying BMF-mediated immune resistance, and explore potential therapeutic strategies for this “immune-excluded” type of tumor. Our findings revealed that “BMF + MC38” mixed-cell subcutaneous tumors lost sensitivity to anti-PD-1 antibody treatment. Furthermore, these mixed-cell subcutaneous tumors exhibited significantly impaired CD8+ T cell infiltration and function, along with an increased proportion of regulatory T cells (Tregs). Higher expression of TGFβ1 was detected in the mixed-cell tumors compared to the MC38 cell tumors. Importantly, either reducing BMF-derived TGFβ1 expression or concurrently targeting PD-1 and TGFβ effectively restored the sensitivity to PD-1 blockade, rescued CD8+ T cell infiltration and function. Additionally, this study revealed that simultaneously targeting PD-1, TGFβ, and VEGFR further suppressed the growth of these mixed-cell subcutaneous tumors. These findings provide a viable combination targeted therapy strategy for the clinical treatment of solid tumors that are insensitive to immunotherapy.</p>

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TGF-β inhibition enhances anti-tumor immunity and sensitizes PD-1 blockade therapy of bone marrow-derived myofibroblasts-induced “immunotherapy resistance” tumor model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月22日

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  • Xin Cheng,
  • Lina He,
  • Cong Zhou,
  • Qingli Li,
  • Baiwen Zhang,
  • Jianzheng Wang,
  • Xiaojiao Cheng,
  • Shuiping Tu

摘要

Resistance to immune checkpoint blockade (ICB) therapy in certain solid tumors remains a major research focus; yet, the underlying mechanisms are not fully understood. Our previous studies demonstrated that subcutaneous tumors formed by a mixture of bone marrow-derived myofibroblasts (BMFs) and tumor cells not only grew faster than those formed by tumor cells alone but were also resistant to ICB therapy. However, the specific mechanism by which BMFs mediate this immune resistance remained unclear. In this study, we established a “BMF + MC38” mixed-cell subcutaneous tumor model to further validate its ICB therapy-resistant phenotype, investigate the mechanism underlying BMF-mediated immune resistance, and explore potential therapeutic strategies for this “immune-excluded” type of tumor. Our findings revealed that “BMF + MC38” mixed-cell subcutaneous tumors lost sensitivity to anti-PD-1 antibody treatment. Furthermore, these mixed-cell subcutaneous tumors exhibited significantly impaired CD8+ T cell infiltration and function, along with an increased proportion of regulatory T cells (Tregs). Higher expression of TGFβ1 was detected in the mixed-cell tumors compared to the MC38 cell tumors. Importantly, either reducing BMF-derived TGFβ1 expression or concurrently targeting PD-1 and TGFβ effectively restored the sensitivity to PD-1 blockade, rescued CD8+ T cell infiltration and function. Additionally, this study revealed that simultaneously targeting PD-1, TGFβ, and VEGFR further suppressed the growth of these mixed-cell subcutaneous tumors. These findings provide a viable combination targeted therapy strategy for the clinical treatment of solid tumors that are insensitive to immunotherapy.