Ferroptosis and the cGAS–STING pathway into precision nano-immuno-theranostics: A mechanistic paradigm for reversing drug resistance in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) represents a formidable therapeutic challenge, with intrinsic and acquired resistance mechanisms severely limiting treatment efficacy and contributing to dismal patient outcomes. This comprehensive review examines the emerging paradigm of precision nano-immuno-theranostics, specifically focusing on ferroptosis-STING coupled platforms as innovative strategies for overcoming multifaceted HCC resistance. This study systematically analyzes five key nanotechnology approaches: lipid nanoparticles (LNPs) for dual-cargo delivery, GPC3-targeted immunotherapeutic platforms, multimodal theranostic systems, sonodynamic therapy constructs, and spatial transcriptomics-guided precision designs. The strategic integration of ferroptosis induction—an iron-dependent cell death mechanism uniquely suited to the iron-rich hepatic microenvironment—with cGAS-STING pathway activation establishes a bidirectional synergistic loop wherein ferroptotic tumor death generates endogenous STING activation, which reciprocally sensitizes cancer cells to ferroptosis. This dual-targeting approach converts immunologically "cold" HCC tumors into inflamed "hot" therapeutic targets, achieving 78–91 % tumor growth inhibition and 4.2–4.8-fold increases in CD8 + tumor-infiltrating lymphocytes in preclinical models, substantially exceeding conventional monotherapies (sorafenib: 45–52 %; checkpoint inhibitors: 35–48 %). Mechanistically, ferroptosis-STING coupling simultaneously addresses three critical resistance modalities: chemoresistance through GPX4/NRF2 axis collapse, immunoresistance via tumor microenvironment reprogramming, and metabolic resistance by disrupting HIF-1α/STAT3-mediated adaptation. Despite compelling preclinical evidence, translation to clinical practice faces substantial challenges in manufacturing scalability, regulatory approval pathways for combination nanotechnology products, biomarker-driven patient stratification, and long-term safety assessment. This review critically evaluates current nano-immuno-theranostic platforms, provides quantitative comparative analysis against existing HCC therapies, identifies critical translational gaps, and proposes strategic solutions spanning adaptive regulatory frameworks, continuous manufacturing innovations, and precision medicine integration. The convergence of nanotechnology, immunotherapy, and multi-omic profiling offers unprecedented opportunities for developing next-generation HCC therapeutics capable of dismantling the complex resistance networks that characterize this aggressive malignancy, with first-in-human trials anticipated in 2025–2027 and potential regulatory approval trajectories extending to 2030.