Nature Study Reveals Immunotherapy May Accelerate Cancer Progression in NASH-Driven Hepatocellular Carcinoma Patients

Hepatocellular carcinoma (HCC) is the primary histological subtype of liver cancer, accounting for primaryLiver Cancer90%. This type of disease is the third most common cause of cancer-related mortality worldwide. Methods such as liver transplantation and hepatectomy are only effective in early-stage HCC, while immunotherapy is regarded as a new hope for treating advanced-stage cancer; however, this therapy has shown only a 15-30% response rate in HCC patients.

A paper titled “NASH limits anti-tumour surveillance in immunotherapy-treated HCC,” led by Dominik Pfister of the biopharmaceutical company Novo Nordisk and published in Nature, reveals the reasons for the differential efficacy of immunotherapy in patients with hepatocellular carcinoma (HCC).

The report indicates that non-alcoholic steatohepatitis (NASH) may be the “primary culprit” behind the lack of benefit from immunotherapy in some patients with hepatocellular carcinoma (HCC). Under the influence of this condition, immunotherapy not only failed to induce tumor regression but even causedTumorThe increase in the number and size of nodules further accelerates cancer progression.

Non-alcoholic fatty liver disease (NAFLD) is a condition associated with insulin resistance andHeredityAcquired metabolic stress-induced liver injury, closely associated with susceptibility, affects over 200 million people worldwide. NASH is a subtype of this condition and a significant driver of HCC.

In this study, researchers fed mice a diet that induces progressive liver injury and NASH for 3–12 months. Single-cell profiling of leukocytes revealed altered immune cell composition in NASH mice, with a significant increase in the number of CD8+PD-1+ cells.

Researchers conducted immunotherapy targeting programmed death protein 1 (PD-1) in NASH mice that had potentially or already developed HCC. The results showed that not only did all existing tumors fail to regress, but hepatic fibrosis in the mice worsened, with liverTumorAn increase in the number of CD8+/PD-1+ T cells within the tissue suggests that activated immune cells may not be fulfilling their role in immune surveillance and instead exhibit potential for tissue damage.

To verify whether activated immune cells promote the progression of NASH-HCC, researchers depleted CD8+ T cells in mice with established NASH that had not yet developed into HCC. They found that CD8+ T cell depletion significantly reduced liver injury and HCC incidence in these mice. In contrast, anti-PD-1 treatment in NASH mice exacerbated liver injury and led to a significant increase in hepatic CD8+ PD-1+ T cells compared with other cell populations.

These data indicate that CD8+ PD-1+ T cells trigger the transition from NASH to HCC in mice, and this transition may be due toTumorImpaired surveillance function and enhanced T cell-mediated tissue injury. This finding was subsequently confirmed in patients with NASH-HCC.

To gain deeper insights into the disruption of immune surveillance in NASH following anti-PD-1 therapy, researchers conducted a meta-analysis of three large-scale, randomized, phase III clinical trials involving immunotherapy for advanced HCC patients—CheckMate-459, IMbrave150, and KEYNOTE-240—and found that immunotherapy demonstrated suboptimal efficacy in patients with non-viral HCC.

Finally, the researchers verified whether anti-PD-1 immunotherapy was ineffective or produced adverse effects exclusively in patients with hepatocellular carcinoma (HCC) caused by non-alcoholic fatty liver disease (NAFLD).

By analyzing data from 130 patients with hepatocellular carcinoma (HCC) receiving anti-PD-1 immunotherapy (13 of whom had non-alcoholic fatty liver disease [NAFLD]), researchers found that NAFLD was associated with shorter overall survival in HCC patients following treatment. This finding was further corroborated by another study involving 118 HCC patients (11 of whom had NAFLD), indicating that patients with underlying non-alcoholic steatohepatitis (NASH) did not benefit from checkpoint inhibitor therapy.

In conclusion, this study demonstrates that immunotherapy exhibits superior efficacy in patients with viral hepatocellular carcinoma compared to those with non-viral hepatocellular carcinoma. This provides clinicians with a basis for tailoring treatment strategies according to the etiology of liver injury and cancer.Liver CancerProvides comprehensive mechanistic insights and a rationale for the stratified treatment of patients, facilitating the development and implementation of personalized cancer therapy regimens.BioValleyBioon.com）