Efficacy and safety of combined RANKL and PD-1 inhibitors in bone metastases: a retrospective study.

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Key findings

• The combination of RANKL inhibitors and programmed cell death protein 1 (PD-1) inhibitors has a favorable safety profile and yields preliminary clinical efficacy in patients with tumor bone metastases. This retrospective analysis provides valuable hypotheses for further research on the combined regimen.

What is known and what is new?

• Bone metastases are a common and intractable complication of advanced malignancies. Monotherapy with PD-1 inhibitors presents limited therapeutic effects in this patient population. RANKL inhibitors are routinely applied to control adverse events associated with bone metastases.

• This study presents novel real-world retrospective evidence demonstrating that the combination of RANKL inhibitors and PD‑1 inhibitors is well tolerated and yields preliminary efficacy in patients with bone metastases, which represents a promising therapeutic combination for this vulnerable patient group.

What is the implication, and what should change now?

• The findings validate the translational rationale for combining bone-targeted agents with immunotherapy in the treatment of malignancies with bone metastases. Well-designed prospective clinical trials are urgently required to confirm the efficacy and clarify the clinical application of this combination regimen.

Introduction

Bone metastases are among the most common sites of metastases in malignant tumors, second only to lung and liver metastases ( 1 , 2 ). The RANKL/RANK/OPG signaling pathway plays a crucial role in regulating osteoclast formation and function ( 3 , 4 ). RANKL inhibitors inhibit osteoclast activation, providing osteoprotective effects that can delay the occurrence of initial skeletal-related events (SREs) and alleviate associated symptoms, such as bone pain. Therefore, they are widely used in the management of bone metastases ( 5 ). In addition to its role in regulating osteoclasts, emerging evidence shows that the RANKL-RANK pathway plays an immunosuppressive role in the tumor microenvironment (TME) ( 6 - 8 ). RANKL-expressing tumor cells induce the upregulation of programmed cell death ligand 1 (PD-L1) and immunoglobulin-like transcript 3 on the surface of dendritic cells (DCs), increase the secretion of immunosuppressive cytokines, and downregulate the expression of major histocompatibility complex class II (MHC II) molecules, thereby impairing the anti-tumor immune effect of DCs ( 9 ). RANKL induces the expression of multiple activating cytokines in DCs, including interleukin (IL)-1, IL-6, IL-12, and IL-15. In addition, the RANK-RANKL pathway has been shown to exert immunosuppressive effects through Treg cells ( 9 , 10 ). These findings support the combination of RANKL inhibitors with immune checkpoint inhibitors, such as programmed cell death protein 1 (PD-1) inhibitors, as potentially offering superior treatment benefits compared to checkpoint inhibitor monotherapy ( 11 , 12 ).

PD-1 inhibitors and RANKL inhibitors represent widely accessible and clinically established anti-tumor agents within current standard-of-care oncological paradigms. Both RANKL and PD-1 inhibitors modulate immune responses. Therefore, there are concerns about potential overactivation of the immune system and increased adverse reactions when these agents are used together. To address this concern and explore the potential clinical use of this combination, we conducted a retrospective analysis to evaluate the safety and efficacy of combined RANKL and PD-1 inhibitor therapy in patients with bone metastases. Efficacy was evaluated based on progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and disease control rate (DCR), aiming to provide new clinical evidence to optimize treatment strategies for patients with cancer and bone metastases. We present this article in accordance with the STROBE reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0312/rc ).

Methods

Data collection and selection

Clinicopathological data for this research were acquired from The Second Affiliated Hospital of Soochow University until February 28, 2024. The clinicopathological data were systematically extracted from institutional electronic health records and transcribed into a secure, 21 CFR Part 11-compliant Electronic Data Capture (EDC) system (Medidata Rave). The structured electronic Case Report Forms (eCRFs) captured variables including medical history, physical examinations, complete blood counts, biochemical and electrolyte measurements, tumor marker assessments, and radiological imaging data. All data were rigorously validated through automated edit checks and strictly anonymized prior to statistical analysis.

The data include medical history, physical examinations, complete blood counts, biochemical and electrolyte measurements, tumor marker assessments, and imaging data. All data were anonymized.

Inclusion criteria

Patients with a confirmed diagnosis of a primary malignant tumor based on pathology and clear radiological evidence or pathological diagnosis of bone metastasis were included. Imaging findings were confirmed by at least two radiology experts. Additionally, patients were included if they received combined treatment with a RANKL inhibitor (denosumab, Xgeva) and a PD-1 inhibitor during their hospital visit, with a time interval of no more than three weeks between the two treatments and a minimum of two treatment cycles.

Exclusion criteria

Patients were excluded if they had clinically significant (i.e., active) cardiac conditions or severe coexisting illnesses that could significantly affect prognosis analysis, a history of immunodeficiency, or were in the acute or chronic phase of tuberculosis infection. Patients with incomplete clinical data or those who could not be adequately followed up were also excluded from the study. Furthermore, to eliminate severe mechanistic confounding variables associated with prior osteoclast modulation, patients with pre-existing metabolic bone diseases (such as severe osteoporosis) who had been treated with bisphosphonates or alternative dosing regimens of RANKL inhibitors prior to, or concurrently with, the initiation of the combined antineoplastic therapy were systematically excluded from the study cohort. This restriction ensured a homogenous immune baseline within the bone microenvironment at the onset of the investigational combination therapy.

Assessment methodology

Efficacy was assessed using the RECIST 1.1 criteria, adapted for real-world application. Imaging assessments were categorized into complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), and not evaluated. DCR and ORR were calculated based on imaging assessments. Adverse events were evaluated using the Common Terminology Criteria for Adverse Events 5.0.

Bone metastatic lesions were measured following the RECIST 1.1 evaluation criteria, which require selecting soft tissue masses with a longitudinal axis diameter of ≥10 mm as target lesions. Lesions that have received radiation therapy were generally not selected as target lesions. PFS was determined from the date of treatment initiation to the date of objective disease progression or death from any cause. OS was determined from the date of treatment initiation to the date of death from any cause. In this study, a significant proportion of enrolled patients (38.6%) had bone metastatic lesions that had been previously treated with radiation therapy. Given that the primary objective of the efficacy analysis to assess overall treatment efficacy, non-bone metastatic lesions were selected for assessment, while bone metastatic lesions were assessed as non-target lesions.

Statistical analysis

SPSS 25.0 software was utilized for statistical analysis. Survival curves were generated using the Kaplan-Meier method, and survival differences between groups were compared using the log-rank test. Recognizing the inherent analytical challenges posed by the non-uniform distribution of baseline clinicopathological characteristics typical of retrospective real-world cohorts [e.g., profound asymmetrical distributions in Eastern Cooperative Oncology Group (ECOG) performance status ratios, solitary versus multiple bone lesion counts, and temporal treatment sequence allocations], unadjusted univariate correlations were interpreted with strict caution. To safeguard statistical robustness and mitigate these underlying confounding imbalances, a Multivariable Cox Proportional Hazards regression model was strategically deployed. This advanced modeling architecture simultaneously adjusts for skewed covariates, ensuring that the derived hazard ratios accurately reflect the independent prognostic magnitude of each evaluated variable. Baseline characteristics among different response groups (CR, PR, SD, PD) were compared using statistical tests such as the Kruskal-Wallis test, one-way analysis of variance (ANOVA), Chi-squared test, and Fisher’s exact test. The log-rank test was used to compare OS among patients with different treatment durations. Results were considered statistically significant when P values were less than 0.05. The handling of missing baseline covariates and incomplete follow-up data was managed via Complete Case Analysis (CCA). Patients lacking critical imaging evaluations required for primary endpoint assessment or essential baseline biochemical data were entirely excluded from the analytical cohort. Given that the overall proportion of missing critical data among potentially eligible records was minimal (<5%), the missingness mechanism was assumed to approximate Missing Completely at Random (MCAR), rendering the application of complex multiple imputation techniques unnecessary for the primary analysis.

Ethics and dissemination

This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of The Second Affiliated Hospital of Soochow University (No. JD-HG-2025-021). All patients provided consent.

Results

Eighty-eight patients with cancer and bone metastasis meeting the inclusion criteria were included in the study ( Figure 1 ). The mean age of the patients at the time of the primary tumor diagnosis was 61.49±11.37 years. Among the patients included, 39.7% had an ECOG score of ≥2. The most common primary tumor site was lung cancer (n=23, 26.1%), followed by breast cancer (n=20 cases, 22.7%) ( Table 1 ). Specifically, 36 patients (40.9%) received the combination as first-line therapy, 20 patients (22.7%) as second-line therapy, 8 patients (9.1%) as third-line therapy, and 24 patients (27.3%) received the combination regimen in the fourth-line setting or beyond. Regarding the specific modalities of prior systemic therapeutic exposures, the historical treatment landscape was diverse. A total of 45 patients (51.1%) had previously undergone systemic cytotoxic chemotherapy regimens, 28 patients (31.8%) had received molecularly targeted therapy (e.g., small molecule kinase inhibitors), and 18 patients (20.5%)—primarily constituting the breast and prostate cancer subsets—had documented prior exposure to endocrine or hormone-deprivation therapies. The median follow-up duration specifically calculated for the final analyzed cohort of 88 patients receiving the combined RANKL and PD-1 inhibitor therapy was 14.0 months [95% confidence interval (CI): 11.6–16.5].

Safety analysis

Among these patients, 61 (76.3%) experienced treatment-related adverse events (TRAEs) of any grade. Grade ≥3 TRAEs were reported in 10 patients (11.4%), including one case of treatment-related immune-related encephalitis leading to death (1.1%) ( Table 2 ). Seven patients (8.0%) discontinued treatment due to adverse events.

Efficacy analysis

Based on the RECIST 1.1 criteria for efficacy assessment, no patients achieved CR, 15 patients (17.9%) achieved PR, 32 patients (36.4%) achieved SD, and 41 patients (46.6%) had PD. The ORR for the entire cohort was 17.0%, and the DCR was 53.4%. Subgroup analysis was conducted to evaluate treatment response by primary tumor site. Among patients with lung cancer, the average number of treatment lines was third-line, with an ORR of 21.7% and a DCR of 43.5%. For breast cancer, the ORR was 20% and the DCR was 60%. Among patients with prostate cancer, the ORR was 28.6%. Analysis of patient characteristics showed that ECOG performance status was statistically significantly associated with treatment response in patients who achieved PR compared to those with SD or PD following treatment with RANKL inhibitors and PD-1 inhibitors (P<0.05) ( Table 3 ).

The median PFS for the entire cohort was 5.90 months (95% CI: 5.13–6.67), and the median OS was 16.10 months (95% CI: 12.67–19.53) ( Figure 2 ). Subgroup analysis was conducted to evaluate survival by primary tumor site. Among patients with lung cancer, the median PFS was 6.30 months (95% CI: 5.75–6.86), and the median OS was 13.20 months (95% CI: 6.22–20.18). For breast cancer, the median PFS was 6.70 months (95% CI: 3.66–9.74). Single-factor analysis of OS revealed that patients with an ECOG score of 0–1 had significantly longer OS compared to those with a score of ≥2 (P=0.01). Also, patients with bone-only metastasis had longer OS compared to those with additional metastatic sites (P=0.007). A baseline serum alkaline phosphatase (ALP) level below 150 U/L is associated with significantly longer OS compared to levels of ≥150 U/L (P=0.02). Additionally, patients who received PD-1 inhibitor prior to RANKL inhibitor had longer OS compared to those who received RANKL inhibitor first (P=0.04) ( Figure 3 ; Table 3 ). To rigorously isolate the systemic pharmacological efficacy of the RANKL and PD-1 inhibitor combination from the potentially profound immunological confounding of radiotherapy-induced immunogenic cell death (e.g., abscopal synergy), a stratified analytical approach was executed. Within the total cohort, 34 patients (38.6%) received concurrent or antecedent palliative radiation therapy targeting bone lesions. Crucially, when subjected to univariate analysis ( Table 4 ), radiation exposure did not emerge as a statistically significant confounder for OS divergence (P=0.45). This lack of confounding indicate that the observed systemic disease control was dominantly driven by the intrinsic efficacy of the combined RANK/PD-1 signaling blockade rather than local radiotherapeutic synergy.

Regarding specific palliative endpoints directly tied to RANKL inhibition, 25 patients (28.4%) experienced SREs over the follow-up trajectory. To further elucidate the bone microenvironmental status, baseline biological parameters were expanded; alongside the prognostic relevance of baseline ALP, the preservation of baseline serum calcium homeostasis demonstrated a consistent, albeit statistically non-significant, trend toward improved overall regimen tolerability and delayed SRE onset.

Multivariate Cox regression analysis was conducted on variables that were significant in the univariate analysis of OS. Consistent with univariate analysis results, ECOG score, bone-only metastasis and baseline serum ALP level were identified as independent influencing factors for OS among patients receiving the combination treatment. Specifically, patients with an ECOG score of 0–1 (P=0.008), bone-only metastasis (P=0.02), and a baseline serum ALP level of <150 U/L (P=0.02) had longer OS ( Table 5 ).

Discussion

Bone metastasis is the third most common site of metastasis in malignant tumors, often accompanied by SREs that severely impact patients’ quality of life and survival ( 13 ). RANKL inhibitors can delay the occurrence of initial SREs and alleviate associated symptoms. Existing evidence suggests that the interactions among bone cells, immune cells, and tumor cells within the bone metastatic microenvironment influence the efficacy of immunotherapy ( 14 ). Therefore, combining PD-1 inhibitors with bone-targeted therapies may offer superior outcomes compared to PD-1 monotherapy. In mouse models of melanoma, prostate cancer and colon cancer, the combination of RANKL and PD-1 inhibitors has shown enhanced anti-tumor effects ( 15 ). An observational study of patients with melanoma and non-small cell lung cancer (NSCLC) receiving a combination therapy of RANKL and PD-1 inhibitors demonstrated DCR of 56% and 58%, respectively ( 16 ).

Additionally, a retrospective study on patients with advanced NSCLC and bone metastases showed that combining PD-1 inhibitors with bone-directed therapy (including palliative radiotherapy and bone-targeted treatment) significantly improved the ORR (34.9% vs. 11.1%, P<0.001) and PFS (8.5 vs. 2.0 months, P=0.002) compared to PD-1 inhibitor monotherapy, highlighting the survival benefit of combination therapy in this population ( 17 ). Another retrospective study involving patients with melanoma and bone metastasis demonstrated that the combination of RANKL and PD-1 inhibitors achieved a 50% ORR, with 62% of patients showing calcification in bone metastatic lesions, indicating effective control of bone metastases ( 18 ). A clinical case report also documented a patient with stage IV melanoma achieving a CR with the combined use of RANKL and PD-1 inhibitors ( 19 ). Another study on the combination of RANKL and PD-1 inhibitors in NSCLC showed that the RANKL + PD-1 inhibitor group had significantly better response rate (40.4% vs. 20.5%, P=0.01), DCR (67.3% vs. 38.7%, P=0.02), OS (14.2 vs. 8.6 months, P=0.02), and real world PFS (7.4 vs. 3.6 months, P<0.01) compared to the non-RANKL + PD-1 inhibitor group ( 20 ). Building on these findings, this study aims to explore the safety and efficacy of this combination, providing further evidence for this potentially more effective combination therapy for malignant tumor bone metastasis. Our preliminary findings suggest that the addition of RANKL inhibitor did not exacerbate the toxicities compared to PD-1 monotherapy. Moreover, it demonstrated promising synergistic effects in terms of efficacy. This could be explained by immune synergism, where the combination of PD-1 and RANKL inhibition enhances anti-tumor immunity through complementary mechanisms. These findings highlight the potential for immune synergy and warrant further investigation in larger clinical trials. Notably, baseline characteristics were not evenly distributed across the response groups (e.g., ECOG performance status differed), which may bias the comparisons. We attempted multivariate Cox regression including these variables, but the small sample size limited statistical power. This potential confounding is acknowledged as a limitation.

In this study, the combination treatment with RANKL and PD-1 inhibitors was generally safe and well-tolerated. Grade ≥3 TRAEs were reported in 10 patients (11.4%), including one case of treatment-related immune-related encephalitis leading to death (1.1%). When compared to bisphosphonates, another class of bone-targeted drugs, RANKL inhibitors offer certain advantages, such as reduced renal toxicity ( 21 - 23 ). In this study, two patients (2.3%) reported grade 1/2 renal dysfunction, and no cases of grade 3 or higher renal toxicities were reported. However, RANKL inhibitors, with a stronger ability to suppress bone resorption than bisphosphonates, are associated with a higher incidence of hypocalcemia ( 24 ). In this study, hypocalcemia occurred in 8 patients (9.1%), including 2 cases of grade 3 hypocalcemia (2.2%). Compared to monotherapy with RANKL inhibitors, no increased risk of hypocalcemia was observed with combination therapy ( 25 ). There were no reported cases of osteonecrosis of the jaw or bone marrow inflammation ( 26 ). A meta-analysis reported that the overall incidence of grade 1–5 TRAEs with various PD-1/PD-L1 immune therapies ranges from 66.4% to 75.1%, with grade 3–4 TRAEs occurring in 14.1% to 19.8% of cases ( 27 ). In this study, the combination of RANKL and PD-1 inhibitors did not significantly increase the overall incidence of TRAEs. These preliminary findings support that the safety profile of the combination treatment is comparable to that of single-agent PD-1 inhibitor treatment. Beyond the standard grading paradigms, the real-world operational tolerability of the combination regimen was comprehensively assessed through detailed treatment modification metrics. Specifically, dose delays directly attributable to TRAEs occurred in 7 patients (8.0%), predominantly secondary to transient transaminase elevations or prolonged severe fatigue. Permanent dose reductions of the PD-1 inhibitor to manage compounding toxicities were necessitated in 5 patients (5.6%). Furthermore, non-elective hospitalizations driven by the severity of treatment-related complications were recorded for 9 patients (10.2%), highlighting the critical need for vigilant proactive toxicity monitoring within this vulnerable bone-metastatic population.

The median PFS for the entire cohort was 5.9 months, with an ORR of 17.0% and a DCR of 53.4%. Notably, 36.4% of patients had received ≥3 lines of prior treatment, making disease control challenging. Further studies with larger sample sizes and more comprehensive data are needed to understand these factors better and refine the assessment of PFS. For example, variations in PFS could be influenced by factors such as microsatellite instability or mismatch repair deficiency, which were not fully clarified in our study. These factors might contribute to the relatively high PFS observed in this study.

Approximately 80% of patients with bone metastases have a primary tumor of breast, lung, or prostate cancer ( 1 ). In this study, lung and breast cancers were the most common primary tumor sites, accounting for approximately 50% of the entire cohort. The median OS for patients with lung cancer after bone metastasis is around 1 year, while for those with breast cancer, prostate cancer, and multiple myeloma, the median OS is approximately 3–5 years after bone metastasis ( 28 ). In clinical trials for advanced NSCLC, ORR for PD-1 inhibitor monotherapy as first-line treatment ranges from 23% to 24.8%, and as second-line treatment, the ORR ranges from 18% to 20% ( 29 - 31 ). Among patients with lung cancer included in this study, the average treatment line was third-line, with an ORR of 21.7% and a DCR of 43.5%, higher than those observed in previous clinical trials for similar patient populations. The median PFS was 6.30 months (95% CI: 5.75–6.86) and the median OS was 13.20 months (95% CI: 6.22–20.18).

In the KEYNOTE-086 study, PD-1 inhibitor monotherapy in second-line or later treatment of breast cancer patients showed an ORR of 5.3%, with a median PFS of 6.70 months (95% CI: 3.66–9.74) ( 32 , 33 ). In comparison, among breast cancer patients included in this study, with an average of four prior treatment lines, we observed a significantly higher ORR of 20% and a DCR of 60%. However, these findings need further confirmation through large-scale, randomized controlled studies.

Prostate cancer has a low level of immune infiltration and is often referred to as a “cold tumor”. However, the combination of PD-1/PD-L1 blocking drugs with other treatments has shown promising results in prostate cancer ( 34 ). A mouse model showed that RANKL blockade increased the effect of PD1/PD-L1 blockade and anti-CTLA4 combination therapy ( 15 ). In the present study, 7 patients with prostate cancer were included in the analysis, achieving an ORR of 28.6%. This suggests that the combination therapy may lead to better treatment outcomes compared to PD-1 inhibitor monotherapy ( 35 ).

Previous research has shown that the sequential administration of PD-1 inhibitors followed by RANKL inhibitors is associated with significantly better treatment outcomes including a more substantial reduction in tumor size, compared to the reverse sequence (P<0.01) ( 14 ). Another clinical study has demonstrated improved survival outcomes when PD-1 inhibitors are administered before RANKL inhibitors ( 16 ). In addition, in a colon cancer model, PD-1 inhibitors increased RANKL expression on activated T cells, suggesting that the RANKL-RANK pathway may play a role as a negative feedback mechanism after the use of immune checkpoint inhibitors ( 15 ). In this study, sequential treatment with PD-1 inhibitors followed by RANKL inhibitors was associated with better OS compared to the reverse sequence (P=0.04). The superior OS trajectory observed when PD-1 inhibitors are sequenced strictly prior to the administration of RANKL inhibitors (P=0.04) can be comprehensively explained by examining the dynamic, temporal shifts in the immunomodulatory architecture of the bone marrow microenvironment. Mechanistically, initial successful blockade of the PD-1 axis triggers robust T cell activation and expansion. However, in response to this hyperactivation, these CD8 + and CD4 + T cells paradoxically upregulate surface expression of RANKL as a potent, compensatory negative feedback mechanism. This excess, T-cell-derived RANKL subsequently interacts with RANK-expressing myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs), thereby invigorating a secondary wave of intense local immunosuppression. By strategically sequencing the RANKL inhibitor immediately following, or concurrent with, PD-1 blockade, the therapeutic antibody precisely intercepts and neutralizes this specific spike in T-cell-derived RANKL ( 36 ). This temporal sequential blockade effectively abrogates the compensatory immunosuppressive loop before it can fully entrench, thereby maintaining and amplifying a sustained anti-tumor immune response—a synergistic peak that is mechanistically missed if RANKL inhibition significantly precedes the onset of immune checkpoint activation.

However, the relatively small sample size in our study limited the ability to perform subgroup analyses across different tumor types, and thus these findings should be interpreted with caution. Further large-scale studies are warranted to validate the impact of treatment sequencing.

Strengths and limitations of this study

This study proposes a novel therapeutic approach for advanced bone metastasis patients via retrospective analysis. The treatment demonstrates a manageable safety profile and shows encouraging efficacy signals.

Despite conducting subgroup analyses across diverse tumor types within this pan-cancer cohort, the limited sample size for specific cancer subtypes remains a constraint. Future prospective clinical trials will address this limitation.

Concolusions

In summary, this study investigated the combination of a PD-1 inhibitor and a RANKL inhibitor for treating bone metastasis. Our results indicate that the combination treatment is well tolerated, and provide evidence of a synergistic effect, warranting further investigation for its application in clinical settings. Notably, among the 88 patients, 30 (34.1%) had previously received concurrent palliative radiotherapy targeting bone metastases. Given the variability in the time intervals between the receipt of radiotherapy and the initiation of combination therapy, it is difficult to independently assess the contribution of radiotherapy based on retrospective data alone; furthermore, given the limited sample size, we are unable to rule out a potential synergistic effect of radiotherapy on patient prognosis. We acknowledge this as a limitation of the present study; future studies should incorporate larger cohorts to further evaluate this interaction. Furthermore, our methodological reliance on CCA for handling sporadic missing data, while justified by the low absolute missingness rate, may have subtly curtailed overall statistical power and introduced latent selection biases, underscoring the absolute necessity for rigorous, pre-specified data capture protocols in future prospective evaluations. Our research team is currently conducting a prospective clinical study ( NCT05435768 ) on the PRaG 2.0 treatment, which combines radiotherapy, PD-1 inhibitors, sequential granulocyte-macrophage-colony-stimulating factor, and IL-2 combination therapy, along with a RANKL inhibitor (PRaG2.0X) for patients with treatment-resistant multiple bone metastatic solid tumors. This study aims to establish the safety and optimal treatment sequence and regimen of the PRaG treatment model in combination with the RANKL inhibitor through phase I clinical trials. Further phase II clinical trials will be conducted to confirm the effectiveness of the PRaG treatment in combination with RANKL inhibitor.

Supplementary

The article’s supplementary files as

Acknowledgments

None.

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0312/rc

Funding: This work was supported by the National Natural Science Foundation of China ( No. 82102824 ), Open Project of State Key Laboratory of Radiology and Radiation Protection of Soochow University ( Nos. GZN1202302 , GZK12025064 , GZK1202238 ), New Medical Technology Project of The Second Affiliated Hospital of Soochow University ( No. 23zl001 ), Multi-center Clinical Research Project for Major Diseases in Suzhou ( No. DZXYJ202304 ), Suzhou Applied Basic Research (Medical and Health) Science and Technology Innovation Project ( No. SYW2024095 ), CNNC Medical Nuclear Medicine Technology Innovation Program Project ( No. ZHYLZD202505 ), the Subject Construction Support Project of The Second Affiliated Hospital of Soochow University ( No. XKTJ-HTD2025003 ), and The Scientific Research Program for Young Talents of China National Nuclear Corporation .

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0312/coif ). The authors have no conflicts of interest to declare.

Data Sharing Statement

Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2026-1-0312/dss 10.21037/tcr-2026-1-0312

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of The Second Affiliated Hospital of Soochow University (No. JD-HG-2025-021). All patients provided consent.

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