Immunotherapy targeting liver cancer tumor-initiating cells: challenges, mechanisms, and emerging therapeutic horizons

Abstract

Liver cancer is a major global health burden, with hepatocellular carcinoma (HCC) being the most common type. Liver cancer tumor-initiating cells (TICs) are responsible for recurrence, metastasis, and therapeutic resistance, thereby presenting formidable treatment challenges. This review provides a comprehensive summary of the biological features of liver cancer TICs, including their potential cellular origins, diagnostic difficulties, key signaling pathways, and complex interactions with the tumor immune microenvironment. Special emphasis is placed on immunotherapeutic strategies, which have shown notable progress but remain limited by TIC-induced immune resistance. The review discusses current approaches such as immune checkpoint inhibitors (ICIs), adoptive cell therapies, and tumor vaccines, as well as combination strategies integrating immunotherapy with chemotherapy, targeted therapy, and locoregional interventions. Furthermore, emerging strategies including gene editing, targeted tyrosine kinase inhibition, and artificial intelligence-based tumor prediction are being explored for their potential to improve therapeutic efficacy. The significance of this review lies in highlighting the importance of surmounting the challenges presented by TICs to boost the efficacy of liver cancer treatment. In conclusion, although existing treatment approaches have demonstrated promise, further research is warranted to elucidate the origins of TICs, establish accurate diagnostic methods, and overcome resistance, ultimately enhancing the efficacy of liver cancer treatment and improving patient outcomes.

Keywords: genome editing; immunotherapy; liver cancer; nanotechnology; non-coding RNAs; therapeutic resistance; tumor microenvironment; tumor-initiating cells.

Figure 1

Molecular mechanisms regulating liver cancer tumor-initiating cells stemness and tumor progression. This figure illustrates the intricate molecular pathways that regulate the stemness and tumorigenic potential of liver cancer tumor-initiating cells (TICs). The interaction between LncTIC1 and β-catenin increases the stability of β-catenin, thereby activating the Wnt/β-catenin pathway. TFAP4 binds to the promoters of DVL1 and LEF1, further enhancing β-catenin stability and activating the expression of downstream genes such as CCND1, CD44, JUN, and TCF1. Additionally, this pathway promotes M2 macrophage polarization, facilitating immune evasion through the secretion of IL-10 and TGF-β. The IL-8 signaling axis, dysregulated in CD133+ liver TICs, contributes to TIC stemness by enhancing MAPK signaling and forming a positive feedback loop via IL-8 and CXCL1. Moreover, epigenetic regulation by non-coding RNAs, such as cia-MAF and lncHOXA10, modulates TIC self-renewal. Circular RNA cia-MAF binds to the MAFF promoter and recruits the TIP60 histone acetyltransferase complex, driving MAFF expression, while the long non-coding RNA lncHOXA10 interacts with SNF2L and recruits the NURF chromatin remodeling complex to the HOXA10 promoter in liver cancer TICs. Finally, SHH signaling, mediated by the PARD3-aPKC interaction, contributes to the upregulation of stemness genes such as SOX2, which correlates with increased stemness and carcinogenesis.