Integrated single-cell multi-omics characterization reveals lipid-associated macrophage-mediated immunosuppression in neoadjuvant immunotherapy of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a cancer with high incidence and mortality rate. Although immune checkpoint inhibitors (ICIs) improved survival outcomes for HCC patients, limited objective response rate highlights the urgency of investigating determinants of immunotherapy. Here, we explore HCC resistance mechanisms following neoadjuvant αPD-1 immunotherapy by constructing a comprehensive multi-modal single-cell transcriptomic atlas consisting of 14 HCC patients treated with αPD-1 from our cohort (ClinicalTrials.gov ID: NCT06571396) and 60 external HCC cases with heterogeneous treatment backgrounds. Supervised by clinical outcomes of our cohort, we identify positive and negative regulators of immunotherapy within the tumor immune microenvironment (TIME), especially lipid-associated macrophages (LAM) with increased lipid metabolic state in non-responders and characterized by C1QA, FABP1, and APOA1 expression. We further show the presence, exogenous inducements and immunosuppressive functions of LAM, along with regulation strategies of its lipid-associated condition, including lycopene and chiglitazar. Furthermore, we construct interaction networks of immune regulators across responders and non-responders, showing distinct ligand-receptor landscapes with intervention targets. We reveal the TIME components including immunosuppressive LAMs that influence immunotherapy outcomes, thus providing evidence and insights for exploring immune landscape and therapeutic strategies for HCC immunotherapy. ClinicalTrials.gov ID: NCT06571396.