Tumour immune barrier determines immunotherapy efficacy in HCC

A tumour immune barrier (TIB) structure formed by the interaction of SPP1⁺ macrophages and cancer-associated fibroblasts (CAFs) appears to influence the efficacy of immunotherapy in patients with hepatocellular carcinoma (HCC), reveals a study.

“Therefore, disruption of the TIB structure by blocking SPP1 may be considered a relevant therapeutic approach to enhance the therapeutic effect of immune checkpoint blockade in HCC,” the researchers said.

Spatial transcriptomics was combined with single-cell RNA-sequencing and multiplexed immunofluorescence to identify the specific spatial structures in the tumour microenvironment (TME), which determine the efficacy of immunotherapy in HCC patients receiving anti-PD-1 treatment.

The researchers discovered a TIB structure—a spatial niche consisting of SPP1⁺ macrophages and CAFs located near the tumour boundary—which facilitated the efficacy of immune checkpoint blockade. They also dissected ligand‒receptor networks among malignant cells, SPP1⁺ macrophages, and CAFs.

Specifically, the hypoxic microenvironment promotes SPP1 expression; SPP1⁺ macrophages interact with CAFs to stimulate extracellular matrix remodelling and promote TIB structure formation, thus limiting infiltration in the tumour core.

Preclinical blockade of SPP1 or macrophage-specific deletion of Spp1 in mice managed to improve the efficacy of anti-PD-1 treatment in mouse liver cancer, as well as reduce CAF infiltration and increase cytotoxic T-cell infiltration.

“These results provide the first key steps towards finding more effective therapies for HCC and have implications for physicians, scientists, and drug developers in the field of HCC,” the researchers said.