Tumor-associated neutrophils attenuate the immunosensitivity of hepatocellular carcinoma

Tumor-associated neutrophils (TANs) are heterogeneous; thus, their roles in tumor development could vary depending on the cancer type. Here, we showed that TANs affect metabolic dysfunction-associated steatohepatitis hepatocellular carcinoma (MASH-related HCC) more than viral-associated HCC. We attributed this difference to the predominance of SiglecF^hi TANs in MASH-related HCC tumors. Linoleic acid and GM-CSF, which are commonly elevated in the MASH-related HCC microenvironment, fostered the development of this c-Myc–driven TAN subset. Through TGFβ secretion, SiglecF^hi TANs promoted HCC stemness, proliferation, and migration. Importantly, SiglecF^hi TANs supported immune evasion by directly suppressing the antigen presentation machinery of tumor cells. SiglecF^hi TAN removal increased the immunogenicity of a MASH-related HCC model and sensitized it to immunotherapy. Likewise, a high SiglecF^hi TAN signature was associated with poor prognosis and immunotherapy resistance in HCC patients. Overall, our study highlights the importance of understanding TAN heterogeneity in cancer to improve therapeutic development.