H19 and the PD-1/PD-L1 Axis in hepatocellular carcinoma and colorectal cancer: emerging evidence, mechanistic links, and therapeutic perspectives

Abstract

Hepatocellular carcinoma (HCC) and colorectal cancer (CRC) are major causes of cancer-related mortality, yet responses to immune checkpoint inhibitors (ICIs) remain heterogeneous. Although programmed death-ligand 1 (PD-L1) is a key component of immune checkpoint biology, antitumor immunity is shaped by multiple tumor-intrinsic and microenvironmental factors, and the contribution of the long non-coding RNA H19 to these processes remains incompletely defined. This narrative review synthesizes experimental and clinical evidence linking H19 to immune regulation in HCC and CRC, with particular emphasis on its potential intersection with PD-L1-mediated immune checkpoint signaling. Evidence was classified as experimentally demonstrated, indirectly supported, contextual, or hypothetical according to the strength, mechanistic resolution, and disease specificity of the available data. Current evidence indicates that H19 perturbation can influence PD-L1-associated phenotypes in selected experimental HCC models; however, a complete, mechanistically resolved H19-dependent PD-L1 regulatory axis, including validated intermediate mechanisms and causal rescue, has not been established in HCC or CRC. Proposed ceRNA and signaling mechanisms remain incompletely validated, while several mechanistic links are supported primarily by indirect or cross-cancer evidence. Beyond direct checkpoint regulation, H19-associated extracellular vesicles and H19-dependent signaling have been implicated in macrophage remodeling, intercellular communication, and T-cell dysfunction, although direct convergence of these processes on H19-mediated PD-L1 regulation remains unproven. Circulating H19 has also shown preliminary associations with tumor presence or burden, but its clinical utility as a diagnostic, prognostic, or predictive biomarker remains insufficiently validated, particularly for ICI response. Overall, H19 represents a biologically plausible interface between non-coding RNA regulation, tumor-intrinsic signaling, and the tumor immune microenvironment rather than an established central regulator of PD-L1. Disease-specific mechanistic studies incorporating H19 perturbation, PD-L1 measurement, pathway-specific rescue, and immune-functional assays are required to determine whether H19 can serve as a clinically actionable component of immune checkpoint regulation.