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

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.