Targeting tumor-associated macrophages to overcome immune checkpoint inhibitor resistance in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) remains a critical global health concern, particularly in regions with high endemicity of hepatitis B, hepatitis C, and non-alcoholic fatty liver disease. Immunotherapy, particularly immune checkpoint inhibitors (ICIs), has emerged as a promising therapeutic strategy for advanced HCC. Despite encouraging results, primary and acquired resistance to ICIs continues to pose significant challenges in clinical practice. Recent research has identified tumor-associated macrophages (TAMs) as key contributors to immune evasion and ICI resistance in HCC, primarily through polarization to the M2 phenotype. M2-polarized TAMs secrete a range of immunosuppressive cytokines that inhibit T cell activation and promote tumor progression through processes such as angiogenesis and epithelial-mesenchymal transition. These mechanisms compromise the efficacy of ICIs and facilitate tumor expansion and metastasis. This review summarizes the role of TAM-related signaling pathways in driving immune evasion and ICI resistance in HCC, with particular emphasis on the contribution of TAM surface receptors and chemokines in immune suppression. Additionally, the review highlights emerging insights into TAM metabolic reprogramming and transcriptional regulation, which have been closely linked to ICI resistance. Furthermore, we explore promising therapeutic strategies targeting TAMs and their associated signaling pathways to enhance ICI efficacy in HCC. Integrating these novel approaches could potentially overcome TAM-driven immune evasion and ICI resistance, boosting the efficacy of immunotherapy and improving patient prognosis in HCC.

Keywords: Hepatocellular carcinoma; Immune checkpoint inhibitors resistance; Immunotherapy; Tumor immune microenvironment; Tumor-associated macrophages.

Fig. 1

Immunosuppressive TME in HCC and ICI resistance. ICI resistance in HCC arises from a multifactorial immunosuppressive landscape. The recruitment of Tregs and MDSCs into the TME suppresses CTL activity. Simultaneously, reduced MHC I/II expression on tumor cells impairs antigen presentation, compromising immune recognition. CTL exclusion is further driven by TME barriers and vascular remodeling. TAMs, predominantly polarized to the M2 phenotype, secrete immunosuppressive cytokines and promote immune-suppressive cell infiltration. Additionally, metabolic reprogramming driven by hypoxia and lactate accumulation further suppresses T cell activity. The overactivation of oncogenic pathways promotes immune escape by hindering both T cell infiltration and function. Collectively, these mechanisms converge to impair ICI efficacy

Fig. 2

Sources and polarization of TAMs in HCC. TAMs play a critical role in shaping HCC TME. TAMs originate from two main sources: bone marrow-derived monocytes and resident Kupffer cells in the liver. Monocytes are recruited to the tumor site by chemokines, where they differentiate into TAMs, while Kupffer cells can be reprogrammed in the tumor context to acquire pro-tumor functions. TAMs exhibit plasticity and can polarize into pro-inflammatory M1 or immunosuppressive M2 phenotypes. M1 macrophages promote anti-tumor immunity by secreting pro-inflammatory cytokines and inducing tumor cell death. In contrast, M2 macrophages suppress immune responses, and support tumor growth, angiogenesis, and metastasis

Fig. 3

Signaling pathways driving TAMs polarization in HCC. In the TME of HCC, multiple signaling pathways drive the polarization of TAMs towards M2 phenotype, further intensifying immune suppression and promoting tumor progression. These pathways alter TAM function and contribute to the creation of a pro-tumor microenvironment that facilitates immune evasion and enhances tumor growth

Fig. 4

TAMs receptors in ICI resistance. (A) TREM2⁺ TAMs in the TME express immunosuppressive signals, leading to CD8⁺T cell exhaustion and reduced PD-1 therapy efficacy. Targeting TREM2⁺ TAMs with anti-Csf1r antibodies enhances PD-1 response. (B) In advanced HCC, TREM1⁺ TAMs, induced by hypoxia, recruit CCR6⁺Tregs and suppress CD8⁺ T cell activity, contributing to resistance to PD-L1 blockade. Blocking TREM1 improves PD-L1 therapy. (C) MARCO⁺ TAMs inhibit IFN-β secretion, impair antigen presentation, and promote immune suppression, contributing to ICI resistance. Combining MARCO inhibition with PD-L1 blockade suppresses liver cancer growth

Fig. 5

TAMs reprogramming in ICI esistance. TAMs drive ICI resistance in HCC through metabolic reprogramming and transcriptional regulation. Loss of WWOX promotes OA synthesis, inducing TAM polarization to the immunosuppressive M2 phenotype, which impairs CD8⁺ T cell function and weakens PD-1 therapy. Inhibition of SCD5 reprograms TAMs and restores anti-tumor immunity. Overexpression of SRSF10 enhances glycolysis and histone lactylation (H3K18la), further polarizing TAMs to M2. Targeting SRSF10 can improve PD-1 therapy. Additionally, PKCα/ZFP64/CSF1 and MYC signaling drive M2 polarization, contributing to immune suppression and ICI resistance. Combining these pathways with PD-1 or CTLA-4 blockade can enhance therapeutic efficacy of HCC, thus diminishing the overall therapeutic response in HCC