IFNα Potentiates Immune-Checkpoint Blockade by Rewiring Metabolic Cross-talk

Immune-checkpoint blockade (ICB) therapy has drastically ameliorated cancer treatment, including the treatment of hepatocellular carcinoma (HCC), a leading cause of cancer death worldwide. Yet there is still an unmet need for improvement, as many patients experience relapse or are unresponsive to ICB monotherapy. This can be partly attributed to the immunosuppressive tumor microenvironment (TME) of HCC, which could support the establishment of resistance to ICB. It is thus crucial to gain a better understanding of the factors influencing the outcome of immunotherapy in order to develop new therapeutic strategies.

IFNα is an interesting potential cytokine for cancer treatment, as it is able to block tumor cell progression by preventing cell-cycle progression and triggering apoptosis. In addition, IFNα favors tumor recognition by immune cells through the promotion of MHC expression on tumor cells (1–3). Murine studies and a clinical trial revealed that combination therapy with IFNα and anti–PD-1 antibodies significantly enhanced tumor control (4, 5). However, the mechanisms behind these promising results remain unclear.

In the study published in this issue, Hu and colleagues revealed that IFNα and anti–PD-1 combination treatment showed remarkable clinical responses in HCC patients, with a 40% overall response rate and an 80% disease control rate (6). To explore the underlying mechanism elicited by the combination therapy, the authors established Hepa1-6 and H22 mouse HCC tumor models and treated the tumor-bearing mice with IFNα or anti–PD-1 alone or in combination. Compared with IFNα or anti–PD-1 monotherapy, the combination therapy further reduced tumor size and delayed tumor progression to a greater extent. Interestingly, IFNα failed to control tumor growth in immunodeficient NCG mice, indicating that the IFNα-mediated antitumor effect is dependent on the immune compartment. Surprisingly, the authors found no significant differences in T, B, myeloid, and natural killer cell frequency within tumors upon treatment. Nevertheless, CyTOF analyses revealed that the tumor-infiltrating CD27⁺ CD8⁺ T-cell subset, which exhibits enhanced cytotoxicity and proliferation signature, was increased upon IFNα monotherapy and upon combination therapy. Unexpectedly, IFNα did not directly promote CD27 expression or proliferation and effector function in CD8⁺ T cells. Instead, the expression of IFNAR1, the receptor of IFNα, was higher in HCC cells than in tumor-infiltrating CD8⁺ T cells, suggesting IFNα may act directly on tumor cells and regulate CD8⁺ T-cell phenotype and function in an indirect manner. Indeed, the knockdown of Ifnar1 in HCC cells abolished the therapeutic effect of IFNα treatment.

Hu and colleagues further uncovered that the HIF1α sig­naling pathway and glycolysis in tumor cells are suppressed upon IFNα treatment. Mechanistically, IFNα signaling downregulated the transcription of FosB, an AP-1 subunit that can interact with HIF1α, thereby enhancing HIF1α target transcription, and decreased glycolysis-related enzyme expression. Furthermore, IFNα-mediated FosB suppression was IRF1 dependent, as IRF1 deficiency abolished the downregulation of FosB and glycolysis-related enzymes. Previous studies demonstrated that tumor cells deprive T cells of glucose (7) and a paucity of glucose can induce T-cell dysfunction (8). Here, the authors showed that IFNα treatment not only increases glucose concentration in the extracellular milieu of HCC but also elevates glycolysis in tumor-infiltrating CD8⁺ T cells with enhanced cytotoxic activity. Of note, a high-glucose environment activates mTOR signaling and further promotes FOXM1 expression, which boosts CD27 expression and activation of CD8⁺ T cells (Fig. 1). In line with the mouse model, increased CD27 expression in tumor-infiltrating CD8⁺ T cells can be observed in responders of cancer patients after treatment, showing the potential of the IFNα and ICB combination in treating patients.

Here, Hu and colleagues propose a novel and promising combination treatment strategy with strong clinical applicability to HCC. Although IFNα has been shown not to act on T cells in the current study, it is well documented that type I IFN can modulate T-cell differentiation and function. Continuous exposure to type I IFN promotes coinhibitory receptor expression in human T cells (9), and prolonged type I IFN stimulation can lead to immune suppression that facilitates immune evasion in cancers (10). These observations imply that IFNα administration could also potentially hinder antitumor responses, and the extent to which it can be applied to other cancers remains to be determined.