Research Progress of SBRT Combined With Immunotherapy in Locally Advanced Head and Neck Cancer

Abstract

The incidence of head and neck cancer ranks sixth among malignant tumors in the world. According to the GLOBOCAN 2020 database, there are about 930,000 new cases and 467,000 deaths per year. Among malignant head and neck tumors, head and neck squamous cell carcinoma (HNSCC) comprises approximately 90% of cases. Between 70% and 80% of HNSCC patients are diagnosed at an advanced stage (III or IV). Following comprehensive treatment, the recurrence rate within 2 years ranges from 40% to 60%. In cases of recurrent or metastatic HNSCC, the median survival period after traditional chemotherapy or targeted therapy is about 1 year, with a 5-year survival rate below 10%. However, several current trials are examining new tactics, such as better prediction biomarkers and combination strategies with chemotherapy, targeted therapy, additional immunotherapy, or radiotherapy, given the relatively poor response rate of immune checkpoint inhibitor monotherapy. Consequently, the research on stereotactic body radiation therapy (SBRT) in conjunction with immunotherapy for locally advanced head and neck tumors is reviewed in this article.

Squamous cell carcinoma of the head and neck (SCCHN) originates from epithelial cells and often occurs in the mouth, pharynx and larynx. In addition to nasopharyngeal carcinoma, most of the risk factors of SCCHN are related to smoking and drinking. Some oropharyngeal cancers are associated with human papilloma virus (HPV) infection.^1–3 High expression of epidermal growth factor receptor (EGFR) is common in SCCHN and is associated with poor survival prognosis. Preclinical studies have shown that tumors with high a expression of EGFR have stronger radioresistance than those with low expression. The addition of anti-EGFR monoclonal antibody (mAb) can increase sensitivity to radiotherapy, which may be related to an induced increase in apoptosis. Treatment with anti-EGFR mAb can enhance radiosensitivity through its effects on cell cycle, DNA damage repair and angiogenesis.^4–6 Therefore, the EGFR mAb, cetuximab, has been approved for the treatment of advanced HNSCC under specific conditions. With the advancement in genomics, researchers have found that the programmed death-1 (PD-1) receptor and its ligand, programmed cell death-ligand-1 (PD-L1), play an important role in maintaining the tumor microenvironment. Numerous studies have shown that the proportion of regulatory T cells (Tregs) in peripheral blood of HNSCC patients increases, and Tregs also express immune checkpoint receptors such as CTLA-4 and PD-1. This indicates that tumor cells begin to establish an immunosuppressive environment in HNSCC patients. In view of the effects on the immune microenvironment in patients with head and neck cancer, the antiprogrammed death-1 (PD-1) immune checkpoint inhibitors nebuliumab and pabolizumab were approved in 2016 for the treatment of patients with relapsed or metastatic HNSCC whose disease had progressed during or after cisplatin chemotherapy. Pabolizumab was approved in 2019 for first-line therapy, either by itself in PD-L1-expressing tumors or in combination with chemotherapy.⁷ However, despite these advancements, patients with advanced HNSCC still have a poor overall survival rate and often experience relapse within 3 to 5 years of receiving platinum-based chemotherapy.⁸ It is crucially important, therefore, to improve the drug response rate in these patients.

To address this goal, recent trials have tested new predictive biomarkers and enrichment procedures in combination with chemotherapy, targeted treatments, other immunotherapies, and radiation therapy (RT). Studies have shown that stereotactic body radiation therapy (SBRT) not only directly kills tumor cells but also induces the expression of various immune molecules, such as heat shock proteins, inflammatory cytokines, cell adhesion molecules, and death receptors.^9–11 These immune molecules can activate local immune surveillance and initiate a systemic immune response, leading to the production of cytokines and circulating CD8+ T cells, which can efficiently inhibit the development of metastatic cancers in nonirradiated areas. This creates an optimal tumor microenvironment for immunotherapy, making SBRT coupled with immunotherapy a promising approach for the management of LA-HNCs.

The combination of SBRT and immunotherapy has shown promising results in enhancing the overall survival and progression-free survival of patients with HNCs. A retrospective study reported the efficacy and safety of nivolumab combined with SBRT in 30 patients with locally advanced oral squamous cell carcinoma who underwent surgical resection within 6 months after treatment.¹² The results showed that the 24-month disease-free survival rate and overall survival rate were 70.4% and 76.4%, respectively. This approach has the potential to improve treatment outcomes and reduce the risk of recurrence, making it a valuable option for patients who may not be suitable candidates for surgery or traditional chemotherapy.

The head and neck play vital physiological roles (speech, swallowing, breathing, sensation, etc.) and serve social functions like appearance, emotion, and expression. Therefore, preserving function and quality of life to the fullest during treatment is crucial. Research indicates that combining SBRT with immunotherapy can enhance pathologic remission rates, reduce the tumor stage, convert nonresectable tumors to resectable ones, and even improve organ preservation. As advancements continue in this area, the combination of SBRT and immunotherapy is poised to be a key player in head and neck tumor treatment. Furthermore, the synergistic effects of SBRT and immunotherapy have shown promising results in terms of overall survival rates and reduced toxicity compared with traditional treatment methods. This combination therapy has the potential to revolutionize the way head and neck tumors are managed, offering new hope and improved outcomes for patients facing these challenging diagnoses. As research progresses and more clinical trials are conducted, the future looks bright for the integration of SBRT and immunotherapy in the treatment of HNC (Fig. 1).

FIGURE 1.

Characteristics of the 3 main treatment modalities. (A) Stereotactic radiotherapy has a high degree of accuracy, the capacity to focus a high radiation dose on a pinpoint area, minimal side effects, and a short radiotherapy cycle. (B) The activation of T cells requires co-stimulation through the TCR/MHC-I complex and the CD28/CD80 signaling pathway. CTLA-4 and CD28 are homologously expressed on the surface of activated CD4 + and CD8 + T cells. The binding of CD80 molecules on antigen-presenting cells (APCs) to CTLA-4 on T cells inhibits T-cell function. Anti-CTLA-4 antibody can block the binding of CTLA-4 to CD80 and prevent its inhibition of T-cell function, thereby preserving the antitumor activity of T cells. The combination of PD-L1 on the surface of cancer cells and PD-1 on the surface of T cells will induce the apoptosis and disintegration of T cells and inhibit the proliferation of T cells. PD-1 inhibitors block the binding of PD-L1 protein to PD-1 receptors, allowing T cells to function normally. (C) SBRT increases the expression of calreticulin and MHC-1, releases DAMPs and HMGB1, and increases the production of reactive oxygen species (ROS). The increased expression of calreticulin can promote the immunogenic death of tumor cells. Increased expression of MHC-1 promotes the recognition of tumor-associated antigens, and the release of HMGB1 and DAMP stimulates the activation of dendritic cells to present tumor-specific antigens, which leads to an increase in ROS, damage to DNA, and cell cycle arrest, as damaged cells cannot be repaired. Enhancement of the immune response by SBRT co-induces the infiltration and aggregation of MDSCs and Tregs, activates APCs, and reduces the infiltration of CD8 ⁺ T cells, thereby transforming tumors from “cold tumors” that are insensitive to immunotherapy into sensitive tumors.

APPLICATION OF SBRT IN TUMOR THERAPY

Radiotherapy is an essential component of cancer treatment. Three-dimensional conformal radiation, proton radiotherapy, intensity-modulated radiotherapy, and stereotactic radiotherapy are among the currently approved radiotherapeutic techniques. By precisely delivering high-dose radiation to a well-defined tumor target in one or a few fractions, stereotactic body radiation treatment (SBRT) can dramatically reduce the dose that surrounding normal tissues receive.¹³ This is also advantageous in local tumor control because a greater physiologically effective dose is reached without harm to healthy tissues. Second, it reduces the length of time patients need to receive care overall, which benefits patients by increasing the availability of treatment facilities while also limiting the postponement of surgery and disease system treatments. Lastly, the high conformal nature of SBRT reduces the risk to nearby organs¹⁴ and its precision reduces the number of treatment sessions, affording greater convenience and comfort to patients. This approach also leads to improved outcomes and minimizes the potential for tumor cell repopulation during the course of treatment. By sparing healthy tissues, SBRT also reduces the occurrence and severity of side effects, contributing to an overall better quality of life for patients undergoing radiation therapy. SBRT has a significant local control rate and a decreased risk of toxicity when compared with surgery or other radiotherapy techniques.¹⁵

Currently, individuals with early NSCLC that is incurable are treated with SBRT as the usual procedure. Patients receive treatment with a greater than 90% local control rate after 3 years, and side effects are minimal.^16–18 SBRT is also a convenient treatment option for patients, as it typically involves fewer treatment sessions and shorter overall treatment times. This makes it a good choice for individuals who may have difficulty adhering to a longer, more intensive treatment schedule. In addition, the precision of SBRT allows for higher doses of radiation to be delivered to the tumor, which can improve patient outcomes. Overall, the benefits of SBRT make it a valuable tool in the fight against cancer. Malignant tumors, either primary or metastatic, frequently affect the liver. For some individuals, surgical resection offers the best chance of recovery, but not all patients are candidates for this procedure. For example, it is not possible to do surgery if the patient has impaired liver function. Patients who frequently have inappropriate surgical scheduling include those with cirrhosis, underlying illnesses, tumors near vascular structures, and locally advanced malignancies.¹⁹ According to a recent meta-analysis, the 2-year local control rate of radiofrequency ablation was 71.8% in hepatocellular carcinoma patients, compared with 83.8% for SBRT patients, and 83.6% and 60% in those suffering from liver metastases.²⁰ It has been shown that SBRT can compensate for the limitations of radiofrequency and lead to an improved rate of local control when treating difficult tumors, like those close to the diaphragm or major blood vessels, as well as large tumors (>3 cm). When it comes to reirradiation or adjuvant therapy for bone metastases with radiation-resistant tissue, SBRT has emerged as the accepted clinical standard. It has the advantage of permitting a stronger therapeutic dose to the targeted location to increase antitumor efficacy without endangering vulnerable organs, like the spinal cord.²¹ Data from a retrospective analysis comparing patients getting SBRT with those receiving standard external radiation treatments showed that at 12 and 24 months, the local control rates were 6.1% versus 28.4% and 14.8% versus 35.6%, respectively. Within a year, the percentage of patients needing further radiation therapy dropped from 15.8% to 2.2%.²² Compared with traditional radiation regimens, patients with spinal metastases who had SBRT had lower chances of local failure and need for reirradiation. With a typical treatment regimen lasting up to 8 weeks, external radiation therapy is a viable treatment option for localized prostate cancer because of the radiobiological characteristics of the disease (slow tumor replication with a low alpha-beta coefficient). Greater local control rates are achieved without the increase in acute toxicity when larger fractional radiation treatments are administered.²³ The currently available, clinically validated, and efficacious SBRT regimens have demonstrated benefits in terms of local control, enhancement of patient-reported quality of life, and reduced levels of toxicity for patients with low- to moderate-risk prostate cancer. The standard dose range is typically given in 5 treatments, ranging from 32.5 to 47.5 Gy.²⁴ A recent comprehensive analysis of 23 research studies on SBRT for high-risk prostate cancer found that there was no increase in negative effects. Furthermore, the 2-year biochemical control rate ranged from 82 to 100 percent, surpassing traditional segmentation protocols.²⁵ SBRT is an advanced method for delivering radiation that allows for the application of high radiation doses to very specific target areas. Increasing clinical data supports the remarkable tolerability and local control rates of SBRT, with many studies showing rates near or above 90%. This establishes SBRT as the standard of care due to its effectiveness and minimal toxicity in treating both primary and metastatic tumors in various clinical settings. By providing a noninvasive treatment option that has no effect on the patient’s quality of life, SBRT is revolutionizing the area of radiation oncology. Both physicians and patients find it an appealing option due to its accuracy and capacity to preserve healthy tissue. SBRT’s prospective uses are growing as technology develops, which strengthens its standing as a key component of contemporary cancer treatment (Table 1).

TABLE 1.

Applications of SBRT and Other Treatment Options to Specific Cancers, With Comparison of Outcomes and References

Tumor type	Treatment	Treatment outcome	Clinical trial	References
Oligometastases of prostate	SBRT	6-mo OS : 97%	Retrospective study	26
Soft tissue sarcoma of head and neck	RT	Median follow-up time:16.6 y	Retrospective study	27
Thymic tumor	SBRT	mPFS:28 mo	Retrospective study	28
Unresectable locally advanced hepatocellular carcinoma	Y90-SIRT	ORR : 71%	DOSISPHERE-01(NCT02582034)	29
T1N0M0 esophageal squamous cell carcinoma	RT	3-y OS : 76.1%	Retrospective study	30

APPLICATION OF IMMUNOTHERAPY IN LOCALLY ADVANCED HEAD AND NECK CANCER

In order to treat cancer, orthopedic surgeon William B. Coley of Memorial Hospital in New York injected germs into the tumor in 1891.³¹ Interleukin (IL)-2 was discovered to be crucial for T-cell development and proliferation in 1974, and Steven Rosenberg and colleagues’ application of IL-2 in cancer treatment was a significant advancement in contemporary tumor immunotherapy.^32–34 One important step in adaptive defense against viruses and tumors is T-cell activation, which primarily occurs by 2 signaling pathways. The initial signal is antigen-specific and is recognized by the T-cell surface receptor (TCR) attaching specifically to the antigen peptide-major histocompatibility complex (MHC).^35–37 The exchange of information between T cells and co-stimulatory molecules (CMs) on the surface of antigen-presenting cells (APCs) mediates the second signal.^38–40 In 1986, researchers discovered that activated T cells contained CD28 molecules, following the discovery of T-cell receptors (TCRs) that are responsible for antigen recognition.^41–43 Later research revealed that T-cell activation necessitated the dual signals of TCR and CD28; CD28 was therefore dubbed a “co-stimulatory molecule.”^44–46 Simultaneously, a protein that bears resemblance to the structure of CD28 was identified by the Pierre Goldstein team.⁴⁷ This protein was named cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and was thought to have the capacity to activate T cells.^48–50 Allison’s group created an antibody against CTLA-4 in 1994, and tested it on a mouse tumor model. They then published the groundbreaking finding that CTLA-4 inhibition could boost antitumor T-cell activity and stop tumor progression.⁵¹ As a result, it was the first instance of evidence that blocking negative immunologic regulatory factors can stop the growth of tumors. Allison subsequently dubbed this technique “immune checkpoint blockade” (ICB).^52–54 Ipilimumab, the first antibody that targeted CTLA-4, became the first immunologic checkpoint (IC) inhibitor when it was licensed in 2011 for the treatment of melanoma.^54,55 These days, most people agree that the immune system is essential for controlling cancer cells, and the mainstays of the anticancer immune system response are T cells and antigen-presenting cells (APCs). The major immune surveillance mediators are cytotoxic T cells. The natural T-cell response, which may target and kill tumor cells, is triggered by the presence of tumor cell antigens.^56–58 The development of HNSCC may be significantly aided by the suppression of this T-cell response, either by immunosuppression or other tumor strategies for immune escape. Growth factor receptors are expressed at high levels in many human tumor cells, and monoclonal antibodies specific to tumor antigens can target these receptors.^59–61 Eighty to ninety percent of HNSCCs have overexpression of EGFR, which is linked to tumor cell proliferation and poor prognosis. Honjo et al made the initial discovery of the programmed cell death receptor-1 (PD-1) gene in 1992, and the programmed cell death receptor ligand-1 (PD-L1) was identified soon thereafter.⁶² In recent years, cetuximab, an IgG1 monoclonal antibody (mAb) targeting EGFR derived from human umbilical cord blood stem cells, has been utilized more frequently to treat cervical squamous cell carcinoma.⁶³ There are 2 primary ways in which mAbs against tumor antigens induce antigen-specific immune responses. NK cells, along with monocytes and neutrophils, can mediate antibody-dependent cytotoxicity, which can trigger tumor lysis directly.⁶⁴ Also, the FcγRs of antigen-presenting cells can interact with tumor antigen-specific mAbs to facilitate tumor opsonophagocytosis and antigen processing. A cytotoxic CD8+ T-cell response specific to the tumor antigen is subsequently triggered.⁶⁵ In 2016, anti-programmed death receptor-1 (PD-1) immune checkpoint inhibitors nivolumab and perbolizumab were approved for the treatment of recurrent or metastatic HNSCC patients with disease progression during or after platinum-based chemotherapy.⁶⁶ The study found that in the KEYNOTE-048 clinical trial, whether it was used alone or in combination with chemotherapy, the overall survival (OS) was improved compared with the previous treatment guidelines. Therefore, since 2019,^67,68 pembrolizumab has been used as a first-line drug (alone or in combination with chemotherapy) to treat cancer patients with positive PD-L1 expression. A little more than 17% of unselected patients did not agree to single-agent PD-1 inhibition as the first-line treatment, despite the possibility that immunotherapy would result in significant and long-lasting antitumor responses. Immunotherapy has completely changed how recurrent and metastatic (R/M) HNSCC is treated. Nivolumab and pembrolizumab, 2 mAbs that block PD-1, increased survival in patients with R/M HNSCC with minimal side effects.^69–71

Immune checkpoint inhibitors have been mentioned numerous times in the past 2 years at ASCO and ESMO conferences in relation to studies on neoadjuvant chemotherapy or concomitant radiation. Nivolumab and Pembrolizumab, either as a single- or 2-cycle induction treatment, have demonstrated some efficacy against locally advanced HNCs.⁷² Clinical trials on immunotherapy plus radiation as a novel adjuvant therapy for postoperative irradiation and chemotherapy are underway for locally advanced head and neck malignancies. These findings suggest a promising direction for the future of cancer treatment, indicating the potential for immune checkpoint inhibitors to play a significant role in enhancing the efficacy of traditional therapies. As researchers continue to explore the synergistic effects of immunotherapy and radiotherapy, the landscape of cancer care may undergo substantial changes, offering new hope for patients with locally advanced head and neck tumors (Table 2).

TABLE 2.

Clinical Trials of Immune Checkpoint Inhibitors for Treatment of Advanced Head and Neck Cancers

Tumor type	Treatment	Treatment outcome	Clinical trial	References
Metastatic triple-negative breast cancer	Pembrolizumab	ORR: 40.8%	KEYNOTE-355（NCT02819518）	73
Squamous non–small-cell lung cancer	Sintilimab	mPFS: 6.7 mo	ORIENT-12（NCT03629925）	74
Advanced esophageal squamous cell carcinoma	Sintilimab	mPFS: 17.4 mo	ORIENT-15（NCT03748134）	75
Resectable non–small-cell squamous cell carcinoma	Duvaliusumab	pCR: 17.2%,	AEGEAN（NCT03800134）	76
Locally advanced cervical cancer	Camrelizumab	ORR: 90%	NACI（NCT04516616）	77

FEASIBILITY AND APPLICABILITY OF SBRT COMBINED WITH IMMUNOTHERAPY FOR LOCALLY ADVANCED HEAD AND NECK CANCER

When treating head and neck squamous cell carcinoma, radiotherapy is crucial (HNSCC). For locally advanced inoperable HNSCC, concurrent radiation in conjunction with radiosensitizing cisplatin chemotherapy is the standard treatment.⁷⁸ As the primary treatment for locally progressed HNSCC, radiation therapy (RT) is an essential component of aggressive treatment that preserves speech and swallowing function in both early and late stages of the illness.⁷⁹ The treatment approach is quickly evolving due to indications that immune checkpoint inhibitors are effective in HNSCC immunotherapy. Immunotherapy has shown promising results in treating HNSCC, particularly in cases where traditional treatments have been less effective.⁸⁰

The use of immune checkpoint inhibitors concurrently with RT and chemotherapy represents a significant advancement in the management of this disease. By targeting specific pathways that suppress the immune response, these inhibitors have the potential to enhance the body’s natural ability to fight cancer cells. As research in this area continues to progress, the integration of immunotherapy into standard HNSCC treatment protocols is likely to play an increasingly important role in improving patient outcomes. Research suggests that applying radiation locally can also boost the immune system’s detection of tumor cells, which in turn can lead to antitumor immunity.⁸¹ By enhancing the immune system’s ability to recognize and attack tumor cells, localized radiation treatment has the potential to not only shrink the targeted tumor but also to provide systemic anticancer effects. This has opened up new possibilities for combining RT with immunotherapy to improve treatment outcomes for cancer patients.

In addition to killing tumor cells and releasing antigens linked to the tumor,⁸² radiation also increases the expression of calreticulin⁸³ and MHC-I molecules on cell surfaces. It releases damage-associated molecular patterns (DAMPs) and high-mobility group box 1 (HMGB1), which may indirectly trigger the activation of dendritic cells, a crucial APC in the anticancer immune response.⁸⁴ In contrast to conventional radiation, SBRT can generate immunogenic cell necrosis through autophagy, aging, and other mechanisms that encourage immune cell infiltration. It can also create ROS, damage DNA, stop the cell cycle, and prevent damaged cells from being repaired. An increasing amount of data indicates that SBRT can trigger an antitumor immune response. The primary mechanisms of this immune activation include the high expression of MHC-I, the release of signals that cause DC maturation, and the release of tumor-associated antigens through immunogenic cell death. Tumor cells may become more susceptible to immune-mediated death as a result of the process. Immunity can also boost antitumor immune activity by acting as an amplifier of the radiation response when combined with SBRT. Increased production of TGF-β by Tregs, DC development into inhibitory antigen-presenting cells (APCs), myeloid-derived suppressor cells (MDSCs) accumulation at the tumor’s perimeter, and the migration of inhibitory Tregs cells into the tumor microenvironment can all result from local radiotherapy and work together to suppress the immune response.^85,86

Hypofractionated radiation therapy can elicit both adaptive immune responses and antigen-specific reactions. T lymphocytes with increased effector function are dispersed across the radiation site and its distal regions. The immune system’s cells are exposed to antigen through the activation of dendritic cells by inflammatory factors, which leads to distant tumor regression and an “in situ vaccine” effect.^87,88 Research by Demaria’s lab has demonstrated that the combination of local radiation and immunotherapy can both suppress the main tumor and have distant effects. Mice treated with RT + 9H10 were observed, and it was found that there was no distant impact in nude mice with T-cell deficit and that CD8+ T cells, rather than CD4+ T cells, were primarily responsible for the suppression of lung metastasis.⁸⁹ Immunotherapy in conjunction with SBRT demonstrated a more pronounced “remote effect,” according to Dewan et al.⁹⁰

Under the current standard treatment of concomitant chemoradiotherapy, only 50% of patients with locally advanced HNSCC survive to see their 5-year posttreatment.⁷⁸ While the overall survival (OS) of patients with HPV-associated oropharyngeal squamous cell carcinoma is good, the 3-year OS for high-risk patients is still only 70%⁹¹ because the severity of the therapy’s side effects limits tolerance of the technique of increasing survival rate through intensive therapy for patients with high-risk disorders. Following 3 years of radiation and chemotherapy, Stamell and colleagues described a case of metastatic melanoma (stage IIIc) with brain metastases. After receiving ipilimumab treatment in addition to intracranial stereotactic radiation, the patient experienced complete remission. Concurrently, an increase in the patient’s serum anti-MAGEA3 antibody titer was discovered, suggesting a potential role for this antibody in the antitumor immune response.⁹² A retrospective review of patients with locally advanced oral squamous cell carcinoma (OSCC) who had surgical resection within 6 months of the diagnosis and were treated with nivolumab plus SBRT between December 2018 and February 2021, revealed a significant MPR of 60.0%, a pCR of 33.3%, and a clinical-pathological downstaging rate of 83.3%. The best survival outcomes were obtained by the neoadjuvant immunotherapy method, which had a 24-month DFS of 70.4% and an OS of 76.4%. It has been demonstrated that this neoadjuvant therapy is safe, well-tolerated, and has manageable adverse events.⁹³ Neoadjuvant pembrolizumab showed promising outcomes in resectable stage III–IV HPV head and neck cancer, with a pathologic response rate of 43% and a clinicopathological downstaging rate of 48%, according to a multicenter phase II trial.⁹⁴ In 2018 and 2019, previously untreated patients with locally advanced HPV-positive and HPV-negative HNSCC were enrolled in the researchers’ single-center phase Ib clinical trial. Neoadjuvant therapy (immunization plus SBRT) was administered to 21 patients. It was well-tolerated and did not delay surgery, therefore fulfilling the main study goal. The frequencies of MPR and pCR were 86% and 67%, respectively, for the entire trial group. In 90% of patients, clinical to pathologic downstaging was in place.⁹⁵ Based on these studies, SBRT plus immunotherapy appears to be a safe and effective combination that may lead to a greater MPR rate and a higher likelihood of clinical to pathologic staging. The results of this phase Ib clinical trial provide promising evidence for the potential of SBRT combined with immunotherapy as a neoadjuvant treatment for locally advanced HNSCC. The high MPR and pCR rates, along with significant clinical to pathologic downstaging, indicate the effectiveness of this treatment approach. Further research and larger clinical trials are warranted to confirm these findings and explore the long-term outcomes of this combination therapy (Table 3).

TABLE 3.

Clinical Trials of Neoadjuvant Immunotherapy

Tumor Type	Treatment	Treatment outcome (%)	Clinical trial	References
Surgically resectable NSCLC	SBRT + tyrlizumab + chemotherapy	MPR:76.1	SACTION-01 (CNT05319574)	96
IA-IIIA NSCLC	SBRT + dulaglizumab	MPR:53.3	NCT02904954	97
HNSCC	SBRT + navuliumab	pCR:90	NCT0324771	98
Triple-negative breast cancer	SBRT + adebelizumab + chemotherapy	pCR:90	NCT05132790	99
Advanced hepatocellular carcinoma	SBRT + sindilizumab	ORR:96	NCT03857815	100

CONCLUSIONS

Because of the nature of tumors and their intricate genesis and progression, it is challenging to attain successful treatment outcomes for locally advanced head and neck cancers; but the combination of immunotherapy and radiotherapy offers a very promising approach to treatment. To improve prognosis, aggressive treatments such as radical surgery and radiation therapy can synergistically achieve tumor downstaging. On the one hand, targeted therapy plus immunotherapy can be applied to the neoadjuvant stage, while, on the other hand, it can also be used to slow the course of the disease and increase the survival of patients with recurring or metastatic cancers. By investing in and conducting additional clinical trials, methods employing SBRT in conjunction with immunotherapy can be developed to enhance the systemic immune response, select appropriate treatment timing and effective predictive markers, adopt lower radiation doses and segmentation modes, and fully utilize the long-term effects of radiation-induced immunity to work in concert against advanced malignant tumors. The effectiveness of this combination therapy has been demonstrated in clinical settings, but its possible toxicity as well as the timing of the sequence of immunotherapy and radiotherapy must be determined through additional clinical trials. So far, there is strong clinical evidence that SBRT in conjunction with checkpoint inhibitor immunotherapy can significantly enhance the systemic immune response, provide flexibility in treatment timing and monitoring with specific predictive markers, minimize the necessary radiation doses by utilizing segmentation modes, and sustain the long-term effects of radiation immunity to work in concert against advanced malignant tumors and metastases. Ongoing research is focused on identifying the optimal patient population for this combination therapy, as well as refining the treatment protocols to maximize efficacy while minimizing side effects. The synergy between SBRT and immunity holds great promise for improving outcomes and quality of life in patients with advanced malignancies, and continued investigation into this approach is crucial for bringing new hope to such patients.