Rewiring Resistance: Integrating TKIs, Dual Checkpoint Blockade, LRT, and Role of CAR-T After ICI Progression in HCC—A Narrative Review

Background/Objectives: Hepatocellular carcinoma (HCC) remains a leading cause of cancer mortality worldwide, due to poor prognosis and limited curative options in advanced stages. Though immune checkpoint inhibitor (ICI)-based combinations have been the first-line therapies, with higher survival compared to tyrosine kinase inhibitors (TKIs), most patients progress within six months and evidence-based guidance for subsequent therapy remains limited. This review summarizes second- and third-line treatment strategies after ICI failure, while highlighting critical research gaps and future advancements needed. Methods: We performed a comprehensive literature review of PubMed, Embase, Cochrane, and major conference proceedings (ASCO, ESMO, AASLD) up to August 2025, including retrospective cohorts, post hoc trial analyses, simulation models, and ongoing prospective trials on second-line therapy in patients with metastatic HCC who progressed on first-line therapy. Discussion and Conclusions: TKIs remain the most widely used second-line option after ICI failure. Lenvatinib, a multi-targeted TKI with strong VEGF inhibition, has shown higher progression-free survival (PFS) compared with sorafenib through tumor vasculature normalization and enhanced T cell infiltration. Other multi-targeted TKIs, like cabozantinib and regorafenib, have shown survival benefits in later line settings. In TKI-refractory or ineligible patients, treatment options are limited, and enrollment in clinical trials is recommended. Retrial of ICIs may be considered in highly selected patients, but evidence remains limited, and this approach is not standard. Concomitant locoregional therapies (LRTs) are useful in oligoprogression where systemic therapy is inadequate, but their integration with systemic therapy is underexplored, and no phase III trials yet define optimal sequencing post-ICI failure. Additionally, we describe novel therapeutic strategies such as chimeric antigen receptor T cell therapy (CAR-T) in HCC.