Background <p>Despite the crucial involvement of the EGFR pathway in hepatocellular carcinoma (HCC), the clinical efficacy of EGFR antibodies in HCC remains uncertain. While existing evidence suggests that immune dysfunction and tumor microenvironment alterations may contribute to treatment resistance, the precise markers underlying this phenomenon in HCC warrant further investigation.</p> Methods <p>In this study, we employed patient-derived xenograft (PDX) models generated from 14 HCC patients enrolled in the REHOPE301 cohort to evaluate the sensitivity to nimotuzumab, a humanized anti-EGFR monoclonal antibody. Whole-exome sequencing (WES) and single-cell RNA sequencing (scRNA) were performed on tumor tissues and tumor-infiltrating lymphocytes (TILs) to elucidate the association between TIL characteristics and EGFR antibody response. In addition, immunofluorescence (IF) staining and flow cytometry were used to validate the findings from scRNA. A predictive risk score and nomogram were subsequently developed using LASSO regression analysis. The prognostic performance of this model was evaluated using 2 external datasets (ICGC-JP and GSE141202) through receiver operator characteristic (ROC) curves and calibration curves analyses.</p> Results <p>Nimotuzumab demonstrated a 50% response rate (7/14) in PDX models. Immune profiling revealed distinct TIL patterns between responders and non-responders. Notably, CD4⁺CCR7⁺ T cells were significantly enriched in resistant tumors (<i>p</i> &lt; 0.001) and negatively correlated with the nimotuzumab response (<i>r</i> = -0.767 <i>p</i> = 0.02). IF analysis revealed a higher proportion of CD4⁺CCR7⁺ double-positive T cells in the non-responder group compared to responders (<i>p</i> = 0.012). In non-responsive tumors, CD4⁺CCR7⁺ T cells exhibited interactions with of macrophages and CD8⁺PDCD1⁺ T subsets. The proportion of CD4⁺CCR7⁺ T showed negative correlations with active CD8 T infiltrations. A reduced infiltration of CD4⁺CCR7⁺ T cells was associated with improved prognosis and enhanced EGFR antibody efficacy across multiple cancer types. Furthermore, a nine-gene signature related to CD4⁺CCR7⁺ T cells was identified as a strong prognostic factor in HCC (HR = 5.19, 95% CI: 3.18–8.46, <i>P</i> &lt; 0.001), and was used to construct a nomogram. WES confirmed prognostic gene mutations (VCAN, CAMK4, and CD226) potentially influencing nimotuzumab response.</p> Conclusions <p>Our findings demonstrate that elevated infiltration of central memory CD4⁺CCR7⁺ T cells in HCC correlates with an immunosuppressive tumor microenvironment, which may contribute to impaired efficacy of EGFR-targeted antibodies and worse clinical outcomes.</p>