Ferroptosis, pyroptosis and necroptosis in hepatocellular carcinoma immunotherapy: Mechanisms and immunologic landscape (Review)

Abstract

Hepatocellular carcinoma (HCC), one of the leading causes of cancer‑related mortality worldwide, is challenging to identify in its early stages and prone to metastasis, and the prognosis of patients with this disease is poor. Treatment options for HCC are limited, with even radical treatments being associated with a risk of recurrence or transformation in the short term. Furthermore, the multi‑tyrosine kinase inhibitors approved for first‑line therapy have marked drawbacks, including drug resistance and side effects. The rise and breakthrough of immune checkpoint inhibitors (ICIs) have provided a novel direction for HCC immunotherapy but these have the drawback of low response rates. Since avoiding apoptosis is a universal feature of cancer, the induction of non‑apoptotic regulatory cell death (NARCD) is a novel strategy for HCC immunotherapy. At present, NARCD pathways, including ferroptosis, pyroptosis and necroptosis, are novel potential forms of immunogenic cell death, which have synergistic effects with antitumor immunity, transforming immune 'cold' tumors into immune 'hot' tumors and exerting antitumor effects. Therefore, these pathways may be targeted as a novel treatment strategy for HCC. In the present review, the roles of ferroptosis, pyroptosis and necroptosis in antitumor immunity in HCC are discussed, and the relevant targets and signaling pathways, and the current status of combined therapy with ICIs are summarized. The prospects of targeting ferroptosis, pyroptosis and necroptosis in HCC immunotherapy are also considered.

Keywords: HCC; ferroptosis; immunotherapy; necroptosis; pyroptosis.

Figure 1

Overview of the molecular mechanisms of ferroptosis. The figure was drawn using Figdraw (www.figdraw.com). ALOX, arachidonate lipoxygenase; BH4, tetrahydrobiopterin; CoQ₁₀, coenzyme Q10; CoQ₁₀H₂, ubiquinol; DHODH, dihydroorotate dehydrogenase; FSP1, ferroptosis suppressor protein 1; GCH1, GTP cyclic hydrolase 1; GPX4, glutathione peroxidase 4; GSH, glutathione; GSSG, glutathione disulfide; I3P, indole-3-pyruvate; IL4i1, IL-4-induced-1; MDR1, multidrug resistance 1; PL, phospholipid; POR, cytochrome P450 oxidoreductase; PUFA, polyunsaturated fatty acid; ROS, reactive oxygen species; SLC7A11, solute carrier family 7 member 11; TFRC, transferrin receptor.

Figure 2

Summary of three molecular mechanisms of pyroptosis, including the typical, atypical and alternative pathway. The figure was drawn using Figdraw (www.figdraw.com). AIM2, absent in melanoma 2; ASC, apoptosis associated dot like protein; CTL, cytotoxic T lymphocyte; DAMP, damage-associated molecular pattern; GSDM, gasdermin; GZM, granzyme; LPS, lipopolysaccharide; -N, N terminal; NLRP, NOD-like receptor family pyrin domain containing; PAMP, pathogen-associated molecular pattern; PRR, pattern recognition receptor.

Figure 3

Core molecular mechanisms of necroptosis. The figure was drawn using Figdraw (www.figdraw.com). cIAP1/2, cellular inhibitor of apoptosis protein 1/2; CYLD, cylindromatosis; DAMP, damage-associated molecular pattern; FADD, Fas-associated death domain; LUBAC, linear ubiquitin chain assembly complex; MLKL, mixed lineage kinase domain-like pseudokinase; P, phosphate group; RIPK, receptor-interacting protein kinase; TNFR, tumor necrosis factor receptor; TRADD, TNFR1-associated death domain protein; TRAF2, TNF receptor-associated factor 2.