Tumor-associated neutrophils attenuate the immuno-sensitivity of hepatocellular carcinoma and curtail immunotherapy response [RNA-Seq]

Tumor-associated neutrophils (TANs) are heterogeneous; thus, their roles in tumor development could vary depending on the cancer type. Here, we showed that TANs were more detrimental to metabolic dysfunction-associated steatohepatitis hepatocellular carcinoma (MASH-related HCC) than to viral-associated HCC. We attributed this difference to the predominance of SiglecFhi 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 TGFß secretion, SiglecFhi TANs promoted HCC stemness, proliferation, and migration. Importantly, SiglecFhi TANs supported immune evasion by directly suppressing the antigen presentation machinery of tumor cells. SiglecFhi TAN removal increased the immunogenicity of a MASH-related HCC model and sensitized it to immunotherapy. Likewise, a high SiglecFhi 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 Overall design: Single, live, immune (CD45+) and tumor cells (CD45-TER119-) cells were sort-purified from the bone marrow, spleen, and tumor of NRAS/AKT HCC-bearing mice for library preparation with Chromium Next GEM Single Cell 5' Reagent Kit v2.