Background: The mechanism of decreased T cells infiltrating tumor tissues in hepatocellular carcinoma is poorly understood.Methods: Cells were separated from the single‐cell RNA‐sequence dataset of hepatocellular carcinoma patients (GSE149614) for cell‐cell communication. Flow cytometry, EDU staining, H3‐Ser28 staining, confocal immunofluorescence staining, western blotting and naked microsubcutaneous tumors were performed for the mechanism of NGF‐NGFR promoting proliferation.Results: The present study has revealed that during the process of T‐cell infiltration from adjacent tissues to tumor tissues, an inefficiency in NGF‐NGFR communication occurs in the tumor tissues. Importantly, NGF secreted by tumor cells interacts with NGFR present on the membranes of the infiltrated T cells, thereby promoting the proliferation through the activation of mitotic spindle signals. Mechanistically, the mediation of mitotic spindle signal activation promoting proliferation is executed by HDAC1‐mediated inhibition of unclear trans‐localization of PREX1. Furthermore, PD‐1 mAb acts synergistically with the NGF‐NGFR communication to suppress tumor progression in both mouse models and HCC patients. Additionally, NGF‐NGFR communication was positively correlates with the PD‐1/PDL‐1 expression. However, expressions of NGF and NGFR are low in tumor tissues, which is responsible for the invasive clinicopathological features and the disappointing prognosis in HCC patients.Conclusion: Inefficiency in NGF‐NGFR communication impairs PD‐1 mAb immunotherapy and could thus be utilized as a novel therapeutic target in the treatment of HCC patients in clinical practice.

The number of T cells that infiltrate tumor tissues in hepatocellular carcinoma (HCC) is significantly low. The molecular mechanism underlying T cell proliferation in tumor tissues is poorly understood. The present study revealed that during the process of T cell infiltration from adjacent tissues to tumor tissues, the NGF-NGFR communication inefficiency occurred in the tumor tissues of HCC patients. Importantly, the tumor cell-secreted NGF interacted with NGFR on the membranes of the infiltrated T cells, which promoted proliferation of these cells through mitotic spindle signal activation. Mechanistically, the mitotic spindle signal activation promoted the proliferation was mediated by the HDAC1 unclear trans-localization-inhibited PREX1 expression. Further, PD-1 mAb acted synergistically with the NGF-NGFR communication to suppress tumor progression in both mouse model and HCC patients. In addition, NGF–NGFR communication was positively correlated with the PD-1/PDL-1 expression. However, NGF and NGFR expressions were low in tumor tissues, which was responsible for the incursive clinicopathological features and the disappointing prognosis in HCC patients. Collectively, the results suggested that NGF-NGFR communication inefficiency impaired PD-1 mAb immunotherapy and could, therefore, be utilized as a novel therapeutic target in the treatment of HCC patients in clinical practice.