POSTN cancer-associated fibroblasts determine the efficacy of immunotherapy in hepatocellular carcinoma.

Objective: Hepatocellular carcinoma (HCC) poses a significant clinical challenge because the long-term benefits of immune checkpoint blockade therapy are limited. A comprehensive understanding of the mechanisms underlying immunotherapy resistance in HCC is imperative for improving patient prognosis.

Design: In this study, to systematically investigate the characteristics of cancer-associated fibroblast (CAF) subsets and the dynamic communication among the tumor microenvironment (TME) components regulated by CAF subsets, we generated an HCC atlas by compiling single-cell RNA sequencing (scRNA-seq) datasets on 220 samples from six datasets. We combined spatial transcriptomics with scRNA-seq and multiplexed immunofluorescence to identify the specific CAF subsets in the TME that determine the efficacy of immunotherapy in HCC patients.

Results: Our findings highlight the pivotal role of POSTN CAFs as potent immune response barriers at specific tumor locations, as they hinder effective T-cell infiltration and decrease the efficacy of immunotherapy. Additionally, we elucidated the interplay between POSTN CAFs and SPP1 macrophages, whereby the former recruits the latter and triggers increased SPP1 expression via the IL-6/STAT3 signaling pathway. Moreover, we demonstrated a spatial correlation between POSTN CAFs and SPP1 macrophages, revealing an immunosuppressive microenvironment that limits the immunotherapy response. Notably, we found that patients with elevated expression levels of both POSTN CAFs and SPP1 macrophages achieved less therapeutic benefit in an immunotherapy cohort.

Conclusion: Our research elucidates light on the role of a particular subset of CAFs in immunotherapy resistance, emphasizing the potential benefits of targeting specific CAF subpopulations to improve clinical responses to immunotherapy.