From local control to immune synergy: the evolving role of stereotactic body radiotherapy in the immunotherapy era of hepatocellular carcinoma

Liver cancer is the third leading cause of cancer-related death worldwide, and its incidence continues to rise (1). Hepatocellular carcinoma (HCC) accounts for 75–85% of these cases (1). The mainstays of HCC treatments include surgery, interventional procedures, and targeted therapy. Radiotherapy has long occupied a peripheral role in the management of HCC, despite its established therapeutic value in patients with macrovascular invasion (MVI), particularly portal vein tumor thrombus (PVTT), where it can reduce tumor thrombus volume and restore portal venous flow (2). Major guidelines have afforded radiotherapy only limited recommendations, owing primarily to the absence of high-level evidence. The NRG/RTOG 1112 trial has marked a turning point, providing the first phase III randomized controlled trial (RCT) evidence that the addition of stereotactic body radiotherapy (SBRT) to sorafenib confers a survival benefit in locally advanced HCC (3). At the same time, immunotherapy is reshaping the treatment paradigm of HCC, and the integration of SBRT with immune checkpoint inhibitors represents a compelling frontier of investigation.

In the NRG/RTOG 1112 trial, SBRT followed by sorafenib significantly improved progression-free survival (PFS) compared with sorafenib alone in patients with locally advanced HCC [9.2 vs. 5.5 months; hazard ratio (HR), 0.55; P<0.001]. After adjustment for stratification factors, overall survival (OS) was also significantly improved (HR, 0.72; P=0.04), with comparable rates of grade ≥3 adverse events between the two groups (42% vs. 47%), indicating that the addition of SBRT did not increase toxicity (3). Although the trial closed early—owing to slow accrual and the shift in first-line standard of care from sorafenib to immunotherapy-based combination regimens—it did not reach its prespecified sample size (achieving 65% rather than the intended 80% power). Nevertheless, the positive PFS result has provided the strongest evidence to date supporting the incorporation of SBRT in selected patients (3). This finding should be interpreted with caution: the reduced statistical power, together with a comparator arm of sorafenib monotherapy that no longer reflects the current first-line standard, means that the magnitude of benefit cannot be directly extrapolated to the contemporary immunotherapy-based era. However, this limitation raises the central question that motivates the present discussion: in an era when immunotherapy-based regimens have become the standard of care, can the addition of SBRT provide incremental benefit, and what is the associated safety profile?

Preclinical studies have demonstrated that SBRT can synergize with immune checkpoint inhibitors through multiple biological mechanisms. SBRT-induced immunogenic cell death enhances antigen accessibility and promotes dendritic cell cross-presentation of tumor antigens (4). At the molecular level, radiation-induced cytosolic DNA activates the cGAS-STING pathway and type I interferon signaling—a central link between radiotherapy and antitumor immunity that promotes dendritic cell maturation and T cell priming (5) (Figure 1). Additionally, radiotherapy can drive T cell polarization toward a Th1 phenotype, augmenting CD8⁺ T cell cytotoxicity, and facilitate effector T cell infiltration into the tumor microenvironment (4). Early clinical experience supports this rationale. Results from the PEMRAD phase II trial demonstrated that among patients with advanced HCC previously treated with sorafenib, SBRT combined with pembrolizumab achieved an objective response rate of 41%, with a grade ≥3 treatment-related adverse event rate of 22% and no treatment-related hepatic decompensation (7). These data provide preliminary evidence supporting the synergistic potential of SBRT combined with immune checkpoint inhibitors. Several phase I/II clinical trials are currently investigating the efficacy and safety of SBRT plus atezolizumab/bevacizumab (NCT05096715, NCT05488522) and SBRT plus durvalumab (NCT04913480). While these early-phase studies will inform feasibility and safety, the ongoing HELIO-RT phase III prospective RCT (NCT07166406) will be the first to compare immunotherapy-based combination regimens with or without SBRT in HCC with MVI, encompassing all current first-line immunotherapy regimens, and may help clarify not only whether SBRT confers additional benefit in the immunotherapy era, but also the nature of that benefit (Table 1).

Figure 1 Immunomodulatory mechanisms of SBRT. Created with BioGDP.com (6). SBRT, stereotactic body radiotherapy.

Beyond whether to integrate radiotherapy and immunotherapy, how to integrate them is an equally critical question. Preclinical studies suggest that the timing, sequencing, and modality of the combination may be key determinants of treatment outcome (4). Regarding the timing of combination therapy, the CARES-009 trial provides instructive insights. In patients with early-stage resectable HCC, perioperative camrelizumab plus apatinib significantly improved event-free survival compared with surgery alone (8). This stands in stark contrast to the consistently disappointing results of adjuvant immunotherapy strategies. Although cohort studies have suggested that adjuvant immunotherapy combined with targeted therapy can improve recurrence-free survival (RFS) in patients with microvascular invasion (9), multiple phase III RCTs have demonstrated that adjuvant immunotherapy fails to confer durable survival benefit. In IMbrave050, the early RFS benefit of adjuvant atezolizumab plus bevacizumab diminished with extended follow-up (10), and results from KEYNOTE-937 presented at the 2026 ASCO GI also showed that adjuvant pembrolizumab did not improve RFS compared with placebo (11). The success of the perioperative approach in CARES-009, mirroring observations in lung cancer and melanoma, is likely attributable to the inclusion of neoadjuvant immunotherapy: the intact tumor serves as an antigen source to fully activate tumor-specific T cells, whereas with adjuvant immunotherapy alone, the primary antigen source has been surgically removed, potentially limiting the capacity of immune checkpoint inhibitors to efficiently prime de novo antitumor T cell responses (12).

This finding also carries implications for the timing of radiotherapy-immunotherapy combinations. If the value of radiotherapy in combination therapy extends beyond cytotoxicity to include antigen release and immune activation through immunogenic cell death, then radiotherapy should be introduced early—while the tumor is still present—to ensure a sufficient antigen source for driving the immune response. The NCT06349317 trial is currently evaluating this concept, investigating neoadjuvant radiotherapy combined with perioperative camrelizumab in patients with resectable HCC accompanied by PVTT. Regarding the optimal sequencing of radiotherapy and immunotherapy, preclinical studies suggest that radiation-induced antigen release can serve as the immune priming stimulus for subsequent checkpoint inhibition; however, administering immunotherapy first may render intratumoral effector T cells susceptible to radiation-induced DNA damage, paradoxically suppressing the expansion of polyfunctional effector T cells (13). Preclinical data therefore suggest that SBRT followed by immunotherapy may be advantageous, although prospective clinical validation is lacking; the optimal order may further depend on the class of immune checkpoint inhibitor used (4), and this question requires further clarification through additional preclinical and clinical studies. The selection of the radiotherapy regimen itself adds another layer of complexity.

In the immunotherapy era, radiotherapy can no longer be designed with cytotoxicity as the sole objective but must also account for immunomodulatory effects, which are related to radiotherapy technique, dose, and fractionation. Complementing SBRT, emerging techniques may address a challenge specific to liver cancer: protecting limited hepatic reserve while enhancing immune activation. FLASH radiotherapy, through the normal-tissue-sparing effect of ultra-high dose rates, could in principle facilitate the dose escalation needed to strengthen immunogenic cell death without precipitating hepatic decompensation, though evidence in abdominal sites remains preclinical and inconsistent (14). Spatially fractionated radiotherapy, which deposits high-dose peaks alongside low-dose valleys, has been associated in preclinical studies with bystander and abscopal immune responses and has been used to treat bulky tumors, a feature potentially relevant to the large lesions often seen in HCC (15). It should be noted that the abscopal effect is rarely seen in clinical practice, and not all radiotherapy-immunotherapy trials have been positive; these rationales await more consistent clinical confirmation. Importantly, the dose and fractionation optimal for tumor ablation may differ from those that best stimulate antitumor immunity. Preclinical work has shown that single-fraction doses above approximately 12–18 Gy upregulate the exonuclease TREX1, which degrades cytosolic DNA and dampens cGAS-STING-driven interferon signaling and the abscopal effect, whereas repeated lower doses optimally prime dendritic cells and CD8⁺ T cells (16). Maximizing local cytotoxicity and maximizing immunogenicity may therefore require different regimens—a tension especially relevant when designing SBRT for combination with immunotherapy. Clinical data for both modalities in HCC nonetheless remain very limited, and their role in radiotherapy-immunotherapy combinations is at present hypothesis-generating.

Beyond optimizing treatment strategies from the standpoint of therapeutic modalities, patient-specific factors warrant careful consideration. Hepatic reserve function is a critical determinant of the feasibility and safety of radiotherapy in patients with HCC. Because most of these patients have underlying cirrhosis, they face competing risks of decompensation from the tumor, the cirrhosis, and treatment itself; SBRT is therefore generally restricted to patients with a Child-Pugh score of 5–7, with dose scaled to the mean liver dose to limit radiation-induced liver disease, and increasingly refined using albumin-bilirubin (ALBI) or Model for End-Stage Liver Disease (MELD) scores or functional imaging. The NRG/RTOG 1112 trial employed individualized radiation doses based on patients’ hepatic function status (3), providing a valuable reference for radiotherapy planning in combined radiotherapy-immunotherapy regimens. In the context of combination therapy, such individualized radiotherapy design is even more important: the radiation dose must be sufficient to induce effective immunogenic cell death and antigen release, yet must not cause hepatic injury that renders patients unable to tolerate subsequent immunotherapy. Striking the optimal balance between these two imperatives remains an unresolved clinical challenge.

Hepatitis virus infection is another consideration that merits attention. An analysis including 1,600 patients with advanced HCC suggested that non-viral HCC may respond poorly to immune checkpoint inhibitors, potentially owing to chronic aberrant activation and functional exhaustion of CD8⁺ T cells (17). However, subsequent analyses from large-scale trials have not consistently confirmed this finding. More importantly, if a subset of non-viral HCC indeed exhibits immunologically “cold” phenotype characteristics, can the immunomodulatory effects of SBRT reshape the tumor microenvironment and convert “cold” phenotype into “hot” phenotype? A recent pilot study using spatial transcriptomics has preliminarily explored this question, suggesting that in patients with HCC, neoadjuvant SBRT followed by atezolizumab plus bevacizumab induced significant and favorable immune remodeling of the tumor microenvironment (18). Beyond spatial transcriptomics, established biomarkers of immune activation—such as PD-L1 expression, tumor-infiltrating lymphocyte density, and interferon-related gene signatures—may offer complementary and more readily deployable means of tracking a cold-to-hot transition. These observations are nonetheless hypothesis-generating rather than confirmatory: they derive from a small-sample translational analysis, and the “cold-to-hot” conversion remains an investigational concept that requires validation in adequately powered, prospective studies. SBRT may thus hold potential as a strategy for overcoming immunotherapy resistance in non-viral HCC. However, no studies have specifically investigated radiotherapy-immunotherapy combinations across HCC with different viral etiologies; even for radiotherapy alone, the NRG/RTOG 1112 trial did not analyze viral infection status as a subgroup (3). Prospective trials with prespecified stratification by viral etiology are needed to address this question.

In the immunotherapy era, for resectable HCC at high risk of recurrence, perioperative immunotherapy incorporating neoadjuvant treatment has shown superiority over adjuvant immunotherapy alone (19,20), though further validation is warranted. For unresectable HCC, immunotherapy-based combination regimens constitute the current first-line standard of care, and the addition of SBRT—particularly in patients with PVTT (3)—represents a promising adjunct to enhance both local control and systemic antitumor immunity (20). For large HCC unsuitable for surgical resection, SBRT offers a viable alternative (21). It has also been employed as a bridge to liver transplantation and as a downstaging strategy for tumors exceeding transplant criteria (22). In the context of conversion therapy, SBRT may reduce tumor burden sufficiently to render initially unresectable tumors amenable to surgery, although the supporting data remain preliminary (23). Furthermore, as immunotherapy continues to prolong patient survival, the use of SBRT for oligometastatic and oligoprogressive HCC is being increasingly explored, with ablative treatment of a limited number of lesions offering the potential to further extend disease control (22).

The role of SBRT in HCC management is no longer confined to the question of whether to add radiotherapy. It now encompasses how best to integrate it, including the optimal timing, sequencing, and radiotherapy parameters, while also accounting for patient-specific factors such as hepatic function, viral etiology, and tumor biology to achieve truly individualized treatment. The role of radiotherapy is expanding along multiple dimensions, extending beyond local cytotoxicity toward immunomodulation, presenting both new challenges and opportunities for the field. Numerous critical questions regarding the integration of radiotherapy and immunotherapy remain to be answered. The NRG/RTOG 1112 trial represents an important step forward; the challenge ahead is to open the door to improved outcomes in HCC.

Acknowledgments

None.

Provenance and Peer Review: This article was a standard submission to the journal. The article has undergone external peer review.

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Funding: This work was supported by the National Key R&D Program of China (2023YFC2411504) and the Peking Union Medical College Hospital Talent Cultivation Program (Category C) (UBJ04712).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-2026-0508/coif). The authors have no conflicts of interest to declare.

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