Hepatocellular carcinoma (HCC) ranks as the fourth leading cause of cancer-related deaths globally [1]. The leading etiological factor for HCC is chronic hepatitis B virus (HBV) infection, responsible for nearly half of all cases worldwide (Fig. 1a). Although the global burden of hepatitis C virus (HCV)-related HCC has decreased due to widespread antiviral therapies, individuals with cirrhosis remain at elevated risk. However, the epidemiological landscape of HCC is shifting, particularly in Western countries, where non-alcoholic steatohepatitis (NASH) has emerged as a rapidly growing contributor [2]. This trend parallels the global rise in metabolic syndrome, with obesity, type 2 diabetes mellitus, and dyslipidemia being significant risk factors in patients with non-alcoholic fatty liver disease (NAFLD). Notably, recent studies have also implicated gut microbiota dysbiosis and chronic systemic inflammation as important contributors to HCC pathogenesis [3] (Fig. 1b). Several demographic and lifestyle factors also independently elevate HCC risk, including male sex, older age, alcohol intake, and tobacco use. Additionally, exposure to environmental carcinogens, such as aristolochic acid, too contributes significantly to disease development [2]. While each of these factors can contribute individually, the risk of HCC appears to rise in a near-exponential manner with the accumulation of multiple risk factors. Thus, understanding the interplay between these diverse etiologies and risk modifiers (Fig. 1c) is essential for refining HCC prevention strategies and optimizing screening protocols, particularly in populations with complex comorbidity profiles.

Immune cells in the liver play a key role in maintaining immune balance and responding to injury or disease. In HCC, this environment undergoes significant changes, with a wide range of fibroblastic and immune cells contributing to tumor development, progression, and spread. The immune tumor microenvironment is composed of innate cells, such as macrophages, neutrophils, dendritic cells, myeloid-derived suppressor cells, mucosal-associated invariant T cells, Natural killer (NK) cells, Natural killer T cells, innate lymphoid cells, and adaptive cells, including CD4 + and CD8 + T cells, regulatory T cells, and B cells [4]. Toll-like receptors (TLRs) are a conserved group of innate immune receptors that serve as the first line of defense by detecting pathogen-associated molecular patterns (PAMPs). Divided into cell surface and endosomal types, TLRs recognize a wide range of microbial signals. Upon activation, TLRs trigger both shared and distinct signaling pathways that guide immune responses [5]. While TLRs are primarily found on immune cells, they are also functionally expressed in various human cancers, including those of the lung, colon, prostate, breast, cervix, and in melanoma. Chronic inflammation, a known cancer risk factor, may contribute to tumor development and progression in part through TLR signaling. TLRs can stimulate cancer cells to release cytokines and chemokines that recruit immune cells and promote anti-tumor responses. However, when TLR signaling is dysregulated, it can instead support tumor growth, invasion, immune evasion, and resistance to therapy. Among TLRs, TLR4 is notably overexpressed in several cancers and is associated with enhanced tumor progression and chemoresistance, though its exact role in tumor biology remains unclear. In HCC, TLR4 overexpression is closely linked to alcohol use and hepatitis C virus infection [6]. Donor TLR4 rs1927914 polymorphism may also be an independent predictor of HCC recurrence and poor survival following liver transplantation [7]. Another study reported that low TLR3 expression is associated with a poor prognosis in HCC [8]. Given the evidence linking TLR signaling to liver inflammation, fibrosis, and malignancy [9], [10], in this review, we examine the role of TLRs in HCC, exploring their contribution to tumor development and progression through modulation of the immune microenvironment. We also discuss the promise of targeting TLR pathways for immunotherapy and highlight the key challenges and future directions in this rapidly advancing area of research.