Efferocytosis as a Metabolic Rheostat: The Metabolic Bridge connecting TKI-induced cell death to immune tolerance in...

Secondary resistance remains a major clinical hurdle in advanced hepatocellular carcinoma (HCC), despite the paradigm shift toward combining tyrosine kinase inhibitors (TKIs) with immune checkpoint inhibitors (ICIs). Existing literature largely focuses on static microenvironmental factors or tumor-intrinsic mutations. The potential role of efferocytosis-driven metabolic reprogramming as a theoretical link between TKI-induced cell death and immune tolerance remains a critical conceptual gap. Addressing this gap, this review proposes the integrative "Metabolic Bridge" framework. We postulate that TKI-induced efferocytosis might operate as a contributor to immune evasion rather than solely a passive clearance mechanism. Synthesizing multi-level evidence, the manuscript suggests that an acute influx of death substrates could exceed macrophage mitochondrial capacity, prompting metabolic diversion. A central component of this hypothesis involves a context-dependent divergence. High metabolic flux in non-steatotic HCC could facilitate an epigenetic lock via lactate-mediated p300 substrate competition (H3K18la). In the setting of NASH-HCC, this same flux might initiate a secondary lipid shift, potentially contributing to immune exclusion and T cell exhaustion. Exploratory transcriptomic analysis indicates that the MERTK-EP300-LDHA signature correlates with poor overall survival (HR=1.6, P = 0.011), providing a clinical rationale for the "Triple-Hit" strategy. This spatiotemporally guided roadmap aims to intercept the efferocytosis window and explore avenues for overcoming therapy resistance. The presented hypotheses guide future experimental validation. This framework shifts the therapeutic focus from a static "death-centric" model to a dynamic "clearance-centric" perspective, aligning with evolving oncological strategies.