Scholarlink

Background <p>Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally, with limited efficacy of current immunotherapy, particularly anti-PD-1 checkpoint inhibitors, due to frequent resistance. CRKL, an adaptor protein involved in oncogenic signaling, has emerged as a novel mediator of immunotherapy resistance.</p> Purpose <p>This review aims to elucidate the molecular and cellular roles of CRKL in HCC, focusing on its contribution to anti-PD-1 resistance via modulation of tumor-associated neutrophils (TANs) and the tumor microenvironment (TME).</p> Main body of the abstract <p>CRKL structurally integrates multiple signaling cascades, including PI3K-AKT, JAK-STAT3, and MAPK pathways, promoting tumor survival, immune evasion, and enhanced PD-L1 expression. It regulates TAN recruitment and polarization towards a pro-tumoral N2 phenotype, augmenting immunosuppression through cytokine production and neutrophil extracellular trap (NET) formation. Clinical data link elevated CRKL expression to poor prognosis and decreased responsiveness to anti-PD-1 therapy. Therapeutic strategies targeting CRKL, including small molecule inhibitors and RNA interference, show promise in overcoming resistance. Additionally, modulation of TAN dynamics represents a complementary approach. Biomarker development integrating CRKL expression and immune parameters holds potential for patient stratification and treatment monitoring.</p> Short conclusion <p>CRKL is a pivotal regulator of immunotherapy resistance in HCC by orchestrating oncogenic and immunosuppressive networks involving TANs. Targeting CRKL and TANs offers a transformative avenue to enhance anti-PD-1 efficacy. Future research should prioritize clinical translation, biomarker validation, and combinatorial regimen optimization to address resistance and improve patient outcomes.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

CRKL as a central mediator of anti-PD-1 immunotherapy resistance in hepatocellular carcinoma: mechanisms and therapeutic perspectives

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年7月7日

查看全文
  • Tamer A. Addissouky

摘要

Background

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality globally, with limited efficacy of current immunotherapy, particularly anti-PD-1 checkpoint inhibitors, due to frequent resistance. CRKL, an adaptor protein involved in oncogenic signaling, has emerged as a novel mediator of immunotherapy resistance.

Purpose

This review aims to elucidate the molecular and cellular roles of CRKL in HCC, focusing on its contribution to anti-PD-1 resistance via modulation of tumor-associated neutrophils (TANs) and the tumor microenvironment (TME).

Main body of the abstract

CRKL structurally integrates multiple signaling cascades, including PI3K-AKT, JAK-STAT3, and MAPK pathways, promoting tumor survival, immune evasion, and enhanced PD-L1 expression. It regulates TAN recruitment and polarization towards a pro-tumoral N2 phenotype, augmenting immunosuppression through cytokine production and neutrophil extracellular trap (NET) formation. Clinical data link elevated CRKL expression to poor prognosis and decreased responsiveness to anti-PD-1 therapy. Therapeutic strategies targeting CRKL, including small molecule inhibitors and RNA interference, show promise in overcoming resistance. Additionally, modulation of TAN dynamics represents a complementary approach. Biomarker development integrating CRKL expression and immune parameters holds potential for patient stratification and treatment monitoring.

Short conclusion

CRKL is a pivotal regulator of immunotherapy resistance in HCC by orchestrating oncogenic and immunosuppressive networks involving TANs. Targeting CRKL and TANs offers a transformative avenue to enhance anti-PD-1 efficacy. Future research should prioritize clinical translation, biomarker validation, and combinatorial regimen optimization to address resistance and improve patient outcomes.