Slamming hepatocellular carcinoma: targeting immunosuppressive macrophages via SLAMF7 reprograms the tumor microenvironment

Abstract

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and one of the leading causes of cancer-related deaths worldwide due to limited treatment options. The tumor microenvironment (TME), which is usually immunosuppressive in HCC, appears to be a decisive factor for response to immunotherapy and strategies aimed at inducing a more inflamed TME hold promise to overcome resistance to immunotherapy. Within the TME, the interplay of various cell types determines whether immunotherapy is successful. Liver macrophages, in particular tumor associated macrophages (TAMs), are known to play a crucial role in tumor progression and represent potential future therapeutic targets. The presence of C-C motif chemokine receptor 2 (CCR2) expressing macrophages is known to be associated with pathogenic angiogenesis and bad prognosis for HCC patients. A recent study published in Cancer Research describes how immunosuppressive macrophages in the TME can be repolarized through targeting Signaling Lymphocyte Activation Molecule Family member 7 (SLAMF7)-regulated CC-chemokine ligand 2 (CCL2) signaling, which sensitizes HCC tumors to immunotherapy in a mouse model. This mini-review gives a brief overview about the current knowledge on SLAMF7 in the context of anti-cancer immunity and how the recent findings could be integrated into new therapeutic strategies for HCC.

Keywords: Hepatocellular carcinoma (HCC); Signaling Lymphocyte Activation Molecule Family member 7 (SLAMF7); combination therapy; tumor microenvironment (TME); tumor-associated macrophages (TAMs).

Figure 1

Schematic diagram illustrating the role of SLAMF7 in the tumor microenvironment of hepatocellular carcinoma. When SLAMF7 expression is low (left side), monocytes are recruited to the tumor site via CCL2/CCR2 and differentiate into tumor-promoting CD68⁺ TAMs. This is associated with high levels of PD-1-expressing CD8⁺ T cells. In contrast, high SLAMF7 expression (right side) leads to downregulation of the MAPK pathway, resulting in reduced production of CCL2 and inhibition of monocyte recruitment. In this context, both TAMs and CD8⁺ T cells display a more proinflammatory phenotype, resulting in better tumor control. SLAMF7, Signaling Lymphocyte Activation Molecule Family member 7; OS, overall survival; CCL2, CC-chemokine ligand 2; CCR2, C-C motif chemokine receptor 2; PD-1, programmed cell death protein 1; TAM, tumor-associated macrophage; MAPK, Mitogen-activated protein kinases; TNF-α, tumour necrosis factor alpha; iNOS, inducible nitric oxide synthase. Created with Biorender.com.