Conversion therapy for HCC includes the conversion of surgically unresectable lesions, such as insufficient volume of the future liver remnant (FLR), to resectable lesions, and it supports the conversion of R1 and R2 resection to R0 resection. Specifically, conversion therapy is characterized by active treatment regimens with a relatively high response rate. Previous studies have shown that radiotherapy, interventional therapy, and targeted therapy can convert 11%~27% of advanced HCC with portal vein tumor thrombus (PVTT) into surgical resection (30–32). ICIs combined with antiangiogenic therapy improved response rates by approximately 24% to 46% with good conversion therapy potential (24, 26, 33). In particular, ICI-based therapy combined with radiotherapy for PVTT has become an important conversion strategy for advanced HCC.

The 5-year recurrence rate after surgery for HCC is as high as 50%~70%, but a standard adjuvant treatment is lacking. ICIs used as adjuvant therapy for patients with high-risk recurrence of HCC are currently a research hotspot, and some phase III clinical studies are underway, including nivolumab (NCT03383458), pembrolizumab (NCT03867084), toripalimab (NCT03859128), atezolizumab combined with bevacizumab (NCT04102098), durvalumab alone or in combination with bevacizumab (NCT03847428), and camrelizumab combined with apatinib (NCT04639180).

Intrahepatic stereotactic body radiation therapy (SBRT) for liver cancer mainly targets small hepatocellular carcinomas (microtumors). A study comparing SBRT with radiofrequency showed that the 3-year overall survival rates were similar (70.4% versus 69.1%), but the 3-year recurrence rates were 5.3% and 12.9%, showing the local control advantage of SBRT (35).

SBRT is a safe and effective bridging therapy in the waiting period prior to transplantation for HCC patients. An analysis comparing SBRT and transcatheter arterial chemoembolization (TACE) and radiofrequency ablation used as bridging therapy before liver transplantation showed similar safety and efficacy (36).

For HCC lesions larger than 5cm, with the double blood supply of the hepatic artery and portal vein, the portal venous blood supply remains intact after single TACE therapy, resulting in a residual tumor. Radiotherapy after TACE can compensate for the deficiency of TACE. A meta-analysis showed that the 3-year survival rates ranged from 24% to 44% for TACE combined with external radiotherapy, an increase of 10%~28% compared to TACE alone (37).

For patients with intermediate or advanced HCC, surgery following neoadjuvant or conversion therapy improved treatment efficacy (32, 38, 39). A meta-analysis that enrolled a total of 2577 patients with unresectable HCC showed that patients who received interventional therapy combined with radiotherapy had improved long-term survival compared with interventional therapy alone. The survival pooled odds ratios at 2, 3, 4, and 5 years were 1.55, 1.91, 3.01, and 3.98, respectively, showing that radiotherapy can significantly improve overall survival, especially long-term survival (40).

Radiotherapy is recommended as neoadjuvant treatment with surgical resection for stage IIIA HCC with PVTT, and it also improved the local tumor control rate and prolonged survival in combination with TACE. A multicenter randomized controlled study enrolled resectable HCC patients with PVTT who were randomly divided into a preoperative neoadjuvant radiotherapy group (82 cases) and a single surgery group (82 cases). The preoperative radiotherapy dose was 18 Gy/6 F for the tumor and PVTT, and surgery was performed 4 weeks after radiotherapy. The results showed that the preoperative radiotherapy group had 1- and 2-year survival rates (75.2% and 27.4%, respectively) that were significantly higher than those in the simple surgical resection group (43.1% and 9.4%, respectively) (41). Another study compared TACE plus radiotherapy with sorafenib in HCC patients with tumor thrombus, the median overall survival was longer in the TACE + radiotherapy group than in the sorafenib group (55 weeks vs. 43 weeks, P=0.04), and PFS (30 weeks vs. 11.3 weeks, P<0.01) (31).

For the majority of central HCC and a small number of peripheral HCC cases, the requirement of a surgical safety margin >1 cm is difficult to meet due to tumor proximity or the involvement of the hilar vascular trunk, even after surgical resection of the tumor. Some patients even have a positive margin, which limits the curative effect of surgery. The Chinese Academy of Medical Sciences reported the results of adjuvant radiotherapy after narrow margin resection of HCC for the first time (42). A total of 181 patients were enrolled, including 33 patients in the narrow-margin surgery combined with postoperative radiotherapy group (Group A), 83 patients in the narrow-margin surgery group who did not receive radiotherapy (Group B), and 65 patients in the wide-margin surgery group (Group C). The 3-year survival rates were 89.1%, 67.7% and 86.0%, respectively, and the 3-year disease-free survival rates were 64.2%, 52.5% and 60.1%, respectively. Furthermore, patients in Groups A and C experienced significantly fewer early recurrences (P = 0.002) and substantially fewer intrahepatic margins (P = 0.048), diffuse recurrences (P = 0.018), and extrahepatic metastases (P = 0.038) than patients in Group B, with no patient developing radiation-induced liver disease. This study preliminarily suggests that postoperative adjuvant radiotherapy can compensate for the lack of narrow-margin surgery.

External radiotherapy for HCC liver lymph node metastasis is safe and effective (43, 44). For adrenal gland metastasis (45), bone or soft tissue metastasis (46), lung metastasis (47), and brain metastasis (48), radiotherapy can also reduce the size of metastases and relieve symptoms, which has clinical benefits.

Most cases of HCC are due to chronic hepatitis infection, which is characterized by a chronic inflammatory state (49). Chronic HBV infection is the main risk factor for HCC in Southeast Asia and Africa, whereas chronic infection with hepatitis C is the main risk factor for HCC in Western countries and Japan (50–54). Among patients with HCC in the United States, approximately 50% to 60% are infected with HCV, 10% to 15% are infected with HBV, approximately 20% to 25% have alcoholic liver disease, and approximately 20% to 30% of patients with HCC have some features of metabolic syndrome (55). Chronic hepatitis infection perturbs the liver microenvironment and tips the scales in favor of carcinogenesis (49). The tumor microenvironment (TME) of HCC is a complex mixture of hepatic nonparenchymal resident cells, tumor cells, immune cells, and tumor-associated fibroblasts. Cytokines and chemokines secreted in the liver can promote angiogenesis, anti-apoptotic responses, and immune evasion, which facilitates an immunosuppressive microenvironment and promotes tumor growth (56, 57). Some studies suggested that the objective response rate (ORR) for PD-1/PD-L1 inhibitors did not significantly differ between virally infected and uninfected HCC patients, the tumor mutational burden was similar between the two groups of patients, and a difference was not observed in the ORR between HBV-HCC and HCV-HCC patients (58, 59).

ICIs have recently revolutionized cancer treatment, while the overall response rates of single ICI therapy are only approximately 20%, which needs further improvement. Several rationales support RT as one of the most encouraging combination strategies. Specifically, RT can augment both antigenicity and adjuvanticity in addition to altering the local TME, which are critical for the immune response. First, radiation induces cell death, which results in cytosolic DNA accumulation, and enhances antigen release in the tumor to activate the production of type I interferon (IFN) genes via the cGAS/STING pathway (60–62). Second, RT promotes the release of tumor antigens and danger-associated molecular patterns (DAMPs), activates antigen-presenting cells (APCs), such as dendritic cells (DCs), and primes T cells within draining lymph nodes (63, 64). Third, radiation helps tumor-infiltrating lymphocytes (TILs) overcome the physical barriers of a tumor and facilitates the adaptive immune response (20, 65, 66). Fourth, reactive oxygen species (ROS) generated during radiation can modify macromolecules, such as proteins and DNA, which increases antigenicity. The presence of oxygen and generation of ROS are critical for direct DNA damage and radiation-induced tissue injury (67). At the same time, RT could change the immunogenicity of tumors from low to high through the increased expression of MHC class I and FAS on tumor cells (66, 68, 69). In addition to the cGAS-STING pathway, the release of DAMPs and cytokines can enhance adjuvanticity, elicit the migration of the pro-anticancer immune subpopulation, alter the TME and tilt the immune response to cancer cell killing. Overall, radiation converts cancer cells into an in situ vaccine to elicit anticancer immunity (70).

Moreover, the addition of ICIs to radiation could help overcome radiation-induced immunosuppressive effects, and ICIs also enhance the RT-induced abscopal effect, referring to the regression of unirradiated tumors (71). Therefore, the synergistic effects of radiotherapy and ICI combinations are diversified ( Figure 1 ).

Numerous preclinical studies and clinical settings have proven the synergistic effects of the combination of ICI and RT (iRT) in various cancer types (72–76). Several clinical studies have shown clinical benefits from iRT therapy. A meta-analysis including 20 clinical trials and 2,027 NSCLC patients showed that iRT therapy was associated with a significantly improved ORR and OS (77). Durvalumab has already been approved as maintenance therapy after chemoradiation therapy for stage III NSCLC patients based on the Phase III PACIFIC trial (78, 79). However, studies on the synergistic effect of HCC are still ongoing. Several preclinical studies have investigated the efficacy and mechanism of iRT in murine HCC models. Kim et al. (80) showed that the combination of anti-PD-L1 and 10 Gy RT significantly suppressed HCC tumor cell growth and improved the survival of tumor-bearing mice compared to those with anti-PD-L1 alone or RT alone, which occurred via IFN-γ/STAT3 signaling. Another preclinical study (81) supported the synergistic effect of the SBRT and anti-PD-1 combination in an orthotopic murine HCC model. The combination of SBRT (30 Gy in 3 fractions) and anti-PD-1 antibodies markedly suppressed tumor growth and improved survival with increased infiltration of CD8+ cytotoxic T cells within the tumor. Another study showed that the ionizing radiation (IR)-induced DNA damage repair (DDR) inhibitor AZD6738 in combination with RT and ICIs in HCC led to stronger immunologic memory, lasting antitumor immunity than radioimmunotherapy, and the prevention of tumor recurrence in mouse models, which relied on the activation of the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) signaling pathway (82). These data showed that the tumor response to radiation can be augmented by concurrent treatment with ICIs. These findings are promising and indicate the potential mechanisms by which combination therapy overcomes immune resistance to generate lasting immunity and protect against tumor recurrence.

In addition to encouraging data in preclinical studies, some published clinical data and case reports have shown promising results regarding the combination treatment of RT and ICIs in HCC. Chiang et al. reported a 100% ORR with SBRT followed by nivolumab for 5 patients with unresectable HCC (83). A phase I trial (NCT02239900) that evaluated liver/lung SBRT with ipilimumab reported that 23% of patients had clinical benefits (84). A retrospective cohort study showed that SBRT combined with a PD-1 inhibitor improves PFS and OS in TACE-refractory patients with intermediate-stage HCC (85). Wonmo Sung’s mechanistic mathematical model showed that for the ICI-RT treatment regimen, the irradiated tumor fraction is the most important parameter for the efficacy, and adding RT to ICI yields an increase in clinical benefit from 33% to 71% in nonirradiated tumor sites for 90% of the tumor cells being irradiated (86). One retrospective study showed that albumin-bilirubin (ALBI) scores and age were independent prognostic factors for PFS and OS in unresectable HCC treated with combined ICIs and RT (87). Radiation-induced liver disease (RILD) is the main adverse effect after liver radiation due to overexposure (88) and typically occurs 4–8 weeks after the termination of RT (89). The key point for preventing RILD is to maintain the liver within the tolerance range limit when designing the RT plan (89). The liver tolerance dose (average dose of the liver) is 23 Gy for Child−Pugh A patients and only 6 Gy for Child−Pugh B patients (90). The ASTRO Clinical Practice Guideline suggests that the selection of dose-fractionation regimen and technique should be based on disease extent, disease location, underlying liver function, and available technologies (34). These trials showed that the most common grade 3/4 treatment-related adverse reactions were elevated AST and ALT levels, colitis, or hand-foot skin reactions attributable to either radiation or immunotherapy, but no patient experienced grade 4 or 5 treatment-related toxicity. Most episodes of toxicity were transient and could be managed (83–85). These studies provide preliminary evidence to show that iRT is safe and efficacious, and they show that systemic immune activation was greater after liver irradiation. Several prospective clinical trials registered at www.ClinicalTrials.gov to evalute the combination of RT and ICIs in HCC are ongoing ( Table 1 ).

ICIs can be administered before, after or even concurrently with RT. Several studies have been performed to determine the optimal sequences of RT and ICIs. The PACIFIC trial showed that durvalumab started within 14 days improved PFS after completing RT (79). One report showed that administering ICIs 7 days after RT was less effective in enhancing OS than concurrent administration (92). Further studies are required to determine the optimal timing of RT to maximize benefits in HCC patients when combined with ICIs.

SBRT or hypofractionated RT is widely accepted to possibly be more immunogenic than conventional fractionated RT with 2 Gy per day. Dewan et al. reported that an 8 Gy × 3 regimen plus anti-CTLA-4 mAb showed better local tumor control and a systemic abscopal effect than two other regimens, 20 Gy × 1 and 6 Gy × 5 (20). A retrospective cohort observation even showed that proton beam radiotherapy (PBT) combined with anti-PD1/PD-L1 provides a sustained and high rate of local tumor control in the irradiation field and an excellent systemic therapeutic effect, resulting in overall tumor control and survival (93). Gaining an understanding of the effect of different fractionations on the immune response is important to improve the combination of RT and ICIs to increase their efficacy and administer personalized ICIs (63).

Finally, appropriate candidates for iRT need to be selected to improve outcomes for HCC patients. PD-L1 expression, tumor mutation burden, and the infiltration of effector T lymphocytes are selectable predictive biomarkers for ICIs in some tumor types but have not been evaluated in HCC (94). The next-generation sequencing-based profiling of immune gene expression signatures, T-cell receptor repertoire, T-cell-inflamed gene expression, and the microbiome is on the way to help identify patients most likely to derive a therapeutic response with HCC (95), not only for predicting susceptibility to ICIs but also individual radiation sensitivity (96–98). Therefore, further efforts to identify appropriate biomarkers to better select patients with HCC who are suitable for iRT are needed.