Sriya Subramanian

Background: Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths.¹ Its prognosis is poor as the five-year survival rate is below 20%, and only 4% for advanced HCC.¹ HCC begins with hepatic steatosis, which induces oxidative stress that injures hepatocytes.¹ This leads to liver fibrosis and eventual cirrhosis, promoting mutations and the formation of dysplastic nodules.¹ While early HCC can be treated with surgical resection, over two-thirds of HCC patients are ineligible for surgery at the time of diagnosis due to metastasis.² These patients must be treated with systemic therapies.² Immune checkpoint inhibitors(ICIs), such as PD-1 inhibitors, are a useful systemic therapy used to treat HCC.² However, only 30% of advanced HCC patients respond to ICI therapy.² The addition of radiotherapy may enhance tumor response to ICIs.³

Research Objectives: This review investigates the mechanisms of ICI resistance and the pathways through which radiotherapy may combat them. We also explore the addition of other drugs that may enhance the efficacy of this combination treatment in certain tumors.

Methods: PubMed was searched from 2024 to 2026 using the MeSH terms “Carcinoma, Hepatocellular”, “Carcinoma, Hepatocellular/radiotherapy”, “Hepatocellular carcinoma: immunotherapy”, and “Carcinoma, Hepatocellular/immunology”.

Results: Although the top 1% most prevalent T-cell clones are similar in both ICI responders and non-responders, they expand to make up over 20% of the total T-cell population in responders while contracting in non-responders.⁴ Responders also have greater expression of certain chemokines, HLA class 2 antigen presentation, and IFN-y expression, allowing them to recruit peripheral T-cells into the tumor where they undergo clonal expansion.⁴ Greater clonal expansion activates a larger and more targeted immune response against the tumor.⁴ The immunosuppressive tumor microenvironment of non-responders can be activated by greater IFN production induced by radiotherapy, promoting greater CD8+ infiltration into the tumor.⁵ In fact, there was a 100% local control rate of 21 anti-PD-1 resistant, advanced stage HCC tumors treated with a PD-1 inhibitor after tumor irradiation.⁶ Additionally, the combination of radiotherapy with PD-1 inhibitors induced greater tumor regression in mice with HCC than either treatment alone through increased ferroptosis induction.⁷ However, it was found that this combination treatment is less effective in TP53 mutant tumors, which make up 27% of HCC tumors. Mutant TP53 leads to activation of the DNA damage response, preventing cGAS-STING activation and subsequent IFN production.⁵ As a result, the addition of DNA damage response (DDR) inhibitors such as MORF4L1 inhibitors may enhance the efficacy of the combination treatment in TP53 mutant tumors.⁸

Conclusion: The combination of radiotherapy with ICIs can improve advanced HCC outcomes by enhancing T-cell recruitment and clonal expansion through IFN production. The addition of MORF4L1 inhibitors may enhance this process in TP53 mutant tumors through suppression of the DDR. Future directions include investigating whether alterations in radiotherapy timing, dosing, and fractionation may improve treatment outcomes.

Works Cited:

1.  Hwang SY, Danpanichkul P, Agopian V, et al. Hepatocellular carcinoma: updates on epidemiology, surveillance, diagnosis and treatment. Clin Mol Hepatol. 2025;31(Suppl):S228-S254. doi:10.3350/cmh.2024.0824
2. Seyhan D, Allaire M, Fu Y, et al. Immune microenvironment in hepatocellular carcinoma: from pathogenesis to immunotherapy. Cell Mol Immunol. 2025;22(10):1132-1158. doi:10.1038/s41423-025-01308-4
3. Ma C, Yu X, Zhang X, Su L, Jiang O, Cui R. Combination of radiotherapy and ICIs in advanced hepatocellular carcinoma: A systematic review of current evidence and future prospects (Review). Oncol Lett. 2025;30(1):342. Published 2025 May 14. doi:10.3892/ol.2025.15088
4. Zhang Y, Tsui YM, Lee JM, Cheung TT, Ho DW, Ng IO. Spatiotemporal dynamics of T-cells in peripheral blood and tumor underlying differential responses to neoadjuvant PD-1 blockade in hepatocellular carcinoma. J Immunother Cancer. 2025;13(12):e013516. Published 2025 Dec 1. doi:10.1136/jitc-2025-013516
5. Cheng CC, Yeh HZ, Sie ZL, et al. Radiotherapy enhances M1 macrophage immunogenic activity through IFNs induction and stimulation in TP53-wild type tumors. Cancer Immunol Immunother. 2026;75(3):71. Published 2026 Feb 7. doi:10.1007/s00262-026-04300-7
6. Tang J, Yang Y, Liu D, et al. Stereotactic body radiotherapy with sintilimab and bevacizumab biosimilar in anti-PD-1 refractory hepatocellular carcinoma: the ReUNION-1 phase 2 trial. Nat Commun. 2025;17(1):823. Published 2025 Dec 18. doi:10.1038/s41467-025-67528-4
7. Dou T, Zhu X, Li H, et al. Radiotherapy combined with anti-PD-1 immunotherapy promotes ferroptosis-driven control of hepatocellular carcinoma. Genes Immun. 2026;27(1):91-105. doi:10.1038/s41435-025-00370-2
8. Wang SW, Hong WF, Huang YL, et al. Targeting MORF4L1-mediated DNA repair potentiates RT-induced antitumor immunity via cGAS-STING activation in hepatocellular carcinoma. Cell Mol Immunol. 2025;22(12):1549-1566. doi:10.1038/s41423-025-01351-1