Oral squamous cell carcinoma (OSCC) is among the deadliest oral cancers, largely due to late diagnoses and limited therapeutic options. In a comprehensive multi-omics study, scientists identified three critical genes—HCK, LILRA4, and PPT1—that are closely linked to OSCC risk, immune regulation, and treatment sensitivity. By combining large-scale genomic data, single-cell analysis, and drug screening, the study highlights how these genes could serve as powerful biomarkers for early detection and personalized treatment. This research lays a scientific foundation for rethinking OSCC diagnosis and therapy through the lens of precision medicine.
Oral squamous cell carcinoma (OSCC) accounts for the vast majority of oral malignancies and continues to pose a serious global health burden. Its rising incidence, particularly in regions with high tobacco and alcohol use, is compounded by persistently poor prognosis due to late-stage diagnosis and limited effective treatments. Despite significant advances in cancer biology, research on OSCC has lagged behind that of other common cancers. The complexity of the tumor microenvironment and lack of specific molecular targets hinder the development of precision therapies. Due to these challenges, there is an urgent need to explore the genetic landscape of OSCC and uncover new biomarkers and therapeutic avenues.
On February 3, 2025, researchers from Chongqing Medical University published (DOI: 10.1016/j.gendis.2025.101552) a new study in Genes & Diseases , unveiling new molecular insights into OSCC. Utilizing data from global genomic and transcriptomic databases, the team conducted a systematic investigation to identify genetic drivers of OSCC. Their work revealed three key genes—HCK, LILRA4, and PPT1—with significant roles in tumor progression, immune dynamics, and drug response. This study marks a significant advancement in our understanding of OSCC and introduces promising candidates for targeted treatment.
The researchers started with a genome-wide analysis of over 315,000 samples using Mendelian randomization, identifying 144 potential gene-OSCC associations. Further refinement narrowed this to 73 gene pairs, and ultimately three standout genes—HCK, LILRA4, and PPT1—were validated across datasets. These genes demonstrated strong associations with OSCC risk and were confirmed through co-localization analysis and single-cell transcriptomic profiling. Single-cell analysis revealed these genes were differentially expressed across eight distinct immune and tumor cell types, implicating HCK in T helper cells, LILRA4 in dendritic cells, and PPT1 in macrophages. Enrichment analyses linked HCK to the Hedgehog and JAK-STAT pathways, LILRA4 to B cell receptor and chemokine signaling, and PPT1 to PI3K-AKT-mTOR and immune signaling pathways.
The team developed a predictive nomogram combining gene expression and clinical data, accurately forecasting 3- and 5-year patient survival. Drug sensitivity analysis revealed correlations between these genes and responsiveness to targeted agents like CHIR99021 and JNK inhibitor VIII, highlighting their utility in personalized OSCC treatment. These integrative findings offer a comprehensive molecular map of OSCC and identify actionable nodes for diagnosis and therapy.
"These findings represent a turning point in oral cancer research," said Dr. Jinlin Song, the study's senior author. "HCK, LILRA4, and PPT1 are not only predictors of disease risk but also gateways to understanding how the tumor communicates with the immune system and responds to treatment. By decoding these pathways, we open the door to therapies tailored to a patient's molecular profile. This study exemplifies the power of data integration and how it can translate into clinical innovation."
The identification of HCK, LILRA4, and PPT1 as OSCC biomarkers and therapeutic targets brings tangible possibilities for clinical application. These genes can aid in early diagnosis, allowing interventions before the disease progresses. Their involvement in immune pathways and chemotherapy response supports their use in designing individualized treatment plans, potentially improving outcomes and minimizing side effects. Looking forward, these findings may accelerate the development of companion diagnostics and targeted drugs. As precision oncology advances, integrating such genetic insights will be vital in reshaping OSCC treatment strategies and offering new hope to patients worldwide.
