Introduction

Pancreatic ductal adenocarcinoma (PDAC), owing to its concealed anatomical location and nonspecific early symptoms, is diagnosed at a metastatic or locally advanced stage in approximately 80% of patients1. Despite with early resection, around 70% of patients will still develop metastatic pancreatic cancer within one year2. Currently, systemic chemotherapy remains the standard treatment for locally advanced or metastatic pancreatic cancer. However, the objective response rate of first-line chemotherapy regimens represented by gemcitabine and albumin-bound paclitaxel or oxaliplatin, irinotecan, 5-fluorouracil and leucovorin (FOLFIRINOX) is less than 40%3. The potential benefit population of targeted therapy for Kirsten rat sarcoma viral oncogene (KRAS) G12 C and poly (ADP-ribose) polymerase pathway is less than 10%, and the prognosis improvement is limited4,5.

In recent years, immunotherapy, particularly immune checkpoint inhibitors (ICIs) such as monoclonal antibodies targeting programmed cell death protein 1 (PD- 1) and its ligand (PD-L1), has been increasingly utilized in the treatment of various solid tumors, leading to significant improvements in patient outcomes6. Nevertheless, for pancreatic cancer, a mere fraction—less than 1%—of patients with mismatch repair deficiency (dMMR) are responsive to immunotherapy, leaving the overwhelming majority of patients confronted with numerous obstacles when undergoing such treatment7. Previous research has demonstrated that the densely fibrotic stroma, limited mutational neoantigen load, and profoundly immunosuppressive microenvironment of PDAC hinder the efficacious infiltration of immunotherapy through the extracellular matrix and impede the recruitment of the local adaptive immune system8,9,10. A phase II clinical trial evaluating the efficacy and safety of Ipilimumab, a monoclonal antibody targeting cytotoxic T lymphocyte-associated antigen- 4 (CTLA- 4), as monotherapy in 27 patients with advanced pancreatic cancer revealed that while the treatment was well-tolerated, its clinical benefit was limited, demonstrating an overall response rate (ORR) of merely 0%11. In a phase IIa clinical trial, 65 patients with advanced pancreatic cancer were recruited. The study revealed that monotherapy with the CTLA- 4 monoclonal antibody tremelimumab yielded no objective responses. However, when tremelimumab was combined with the programmed cell death ligand 1 (PD-L1) monoclonal antibody durvalumab, a modest yet promising objective response rate (ORR) of 3% was observed. Notably, the single-agent strategy failed to elicit any objective responses12. The above studies indicate that neither single-agent nor dual-agent ICI therapy has brought benefits to patients. Recently, research focusing on transforming “cold” tumors into “hot” tumors by remodeling the immune microenvironment in response to the abnormally rich tumor stroma observed in pancreatic cancer has emerged as a prominent area of interest. Novel combination therapies, including immunotherapy integrated with chemotherapy13, targeted therapy14, chimeric antigen receptor T-cell (CAR-T) technology15, and tumor vaccines16, have demonstrated promising safety profiles in early clinical trials. The study by Padrón et al.17indicated that in a Phase II clinical trial, the combination of Nivolumab with gemcitabine and nab-paclitaxel significantly improved the one-year survival rate of patients compared to the use of gemcitabine and nab-paclitaxel alone (57.7% vs. 35%). A retrospective study presented at ASCO 2020 showed that Toripalimab combined with chemotherapy as a first-line treatment for advanced PDAC resulted in a median progression-free survival (PFS) of 7.0 months18. The study conducted by Zhang et al.19 revealed that the combination of PD- 1 inhibitors and AG chemotherapy has exhibited remarkable efficacy and safety as a first-line treatment for patients with advanced PDAC. Notably, this therapeutic regimen also significantly enhanced overall survival in patients harboring co-mutations of KRAS and TP53. Consistent results were observed in a retrospective study condubted by Cheng et al.20, which suggested that the PFS and OS of paitents receiving the combination of immunotherapy and chemotherapy were significantly superior to those of treated with chemotherapy alone, while adverse reactions remained manageable. In summary, while there currently lacks high-caliber prospective randomized controlled clinical evidence to substantiate that patients with pancreatic cancer unequivocally benefit from the combination of immune checkpoint inhibitors (ICI) and chemotherapy, ongoing real-world studies persist in exploring this approach owing to the relatively favorable safety profile and tolerability of ICI therapy.

This retrospective study endeavors to elucidate the clinical efficacy of PD- 1 inhibitors in conjunction with chemotherapy regimens—specifically, the Gemcitabine and albumin-bound paclitaxel combination (henceforth referred to as the AG regimen), and the Oxaliplatin, Irinotecan, 5-FU, and calcium leucovorin quartet (known as the FOLFIRINOX regimen)—as compared to chemotherapy alone (either the AG or FOLFIRINOX regimen) in the management of advanced pancreatic cancer. Moreover, this study aims to comprehensively investigate the diverse factors that influence the therapeutic efficacy of the combination of immunotherapy and chemotherapy. This research will provide valuable insights and guidelines for identifying the most suitable patient population for this integrated treatment approach.

Methods

Study design and patients

This is a single-center, retrospective, observational study that included patients with histologically or cytologically confirmed unresectable locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC) who received systemic treatment at the First Affiliated Hospital of Bengbu Medical University between January 2022 and June 2024. Patients were categorized into two groups based on their treatment regimens: the chemotherapy-alone group, whih included 29 patients (25 on the AG regimen and 4 on the FOLFIRINOX regimen), and the immunotherapy plus chemotherapy group, which comprised 28 patients (6 received tislelizumab in combination with FOLFIRINOX, 16 received tislelizumab with AG, 4 received sintilimab with AG, and 2 received camrelizumab with AG). This study received approval from the Ethics Committee of the First Affiliated Hospital of Bengbu Medical University and was conducted in strict adherence to the principles outlined in the Declaration of Helsinki. The requirement for written informed consent was waived, as this study utilized a retrospective design.

The primary inclusion criteria were: (1) histopathological or cytological examination confirmed the diagnosis of PDAC; (2) locally advanced or metastatic PDAC deemed unresectable based on imaging evaluations; (3) at least one lesion was quantifiable; 4)ECOG score of ≤ 1; 5) the primary organ functions, including liver, kidney, and cardiac function, were within normal limits; 6) patients have undergone a minimum of two full treatment cycles; 7) the patient has not received any anti-tumor drug treatments, including chemotherapy or immunotherapy, in the past.

The exclusion criteria were; (1) patients who had received previous chemotherapy or immunotherapy with CTLA- 4 inhibitors or PD- 1/PD-L1 inhibitors; (2) patients with recent systemic active infection or an acute exacerbation of a chronic disease, rendering them unable to tolerate chemotherapy; (3) previous autoimmune disease or a condition that necessitates immunosuppressive therapy to achieve the desired level of immunosuppression; (4) patients with malignancies other than pancreatic cancer or those with severe, uncontrolled conditions; (5) patients with incomplete follow-up data.

Treatment administration

For the chemotherapy-alone group, patients received AG (nab-paclitaxel at a dose of 125 mg/m2 and gemcitabine at a dose of 1000 mg/m2 intravenously on days 1 and 8 of each 21-day cycle) or modified FOLFIRINOX (consisting of intravenous infusion of oxaliplatin at 85 mg/m², intravenous infusion of leucovorin at 400 mg/m², intravenous infusion of irinotecan at 135–150 mg/m², intravenous bolus of 5-fluorouracil at 400 mg/m², and a continuous 46-hour intravenous infusion of 5-fluorouracil at 2400 mg/m² on day 1 of each 14-day cycle) regimens. For the immunotherapy plus chemotherapy group, patients received PD- 1 inhibitors every 21 days in accordance with the aforementioned treatment regimen. The PD- 1 inhibitors selected in this study include three types: Camrelizumab (200 mg, supplied by Hengrui Pharma Co., Ltd., Jiangsu, China), Tislelizumab (200 mg, supplied by BeiGene Shenzhou Biotechnology Co., Ltd., Beijing, China), and Sintilimab (200 mg, supplied by Cinda Biopharmaceutical Co., LTD., Suzhou, China). Treatment was continued until disease progression or the occurrence of intolerable toxicity. All patients underwent CT scans or MRIs every two cycles to evaluate treatment efficacy. Hematological parameters were monitored during each treatment cycle.

Data collection and follow up

Follow-up assessments were conducted via the hospital’s inpatient and outpatient medical record systems as well as through telephone calls, continuing until December 2024 or until the patient’s death. Factors potentially related to patient outcomes were systematically collected, including gender, age, ECOG performance status, presence of distant metastasis, treatment regimen, pre-treatmentCEA, CA19 - 9 and SOD levels, changes in CEA, CA19 - 9 and SOD levels at 8 weeks post-treatment, therapeutic efficacy, and adverse events (AEs). Patients who did not attend outpatient follow-ups or were not hospitalized were contacted via telephone for follow-up every three months. The reference ranges for the relevant biomarkers included in the assessment were determined as follows: Carcinoembryonic antigen (CEA) 0–5 ng/ml; Carbohydrate antigen 199 (CA199) 0–37 IU/ml; Superoxide dismutase (SOD) 129–216 KU/L. In the analysis, all indicators were considered as binary variables: SOD was dichotomized based on the median (154 KU/L); CEA was dichotomized based on the upper limit of the normal reference range (5 ng/ml); CA199 was dichotomized according to its clinial signifcance from the upper limit of blood test (37 IU/ml).

This study was conducted in accordance with the principles of the Declaration of Helsinki. All data acquisition was approved by the Ethics Committee of our hospital.

Efficacy and safety analysis

The primary endpoint of this study was progression-free survival (PFS), defined as the time from treatment initiation to disease progression or death. The secondary endpoints comprised overall survival (OS), defined as the time interval from the start of treatment to death from any cause; objective response rate (ORR), defined as the proportion of patients achieving a best overall response of either complete response (CR) or partial response (PR); and disease control rate (DCR), defined as the proportion of patients achieving CR, PR, or stable disease (SD). Objective efficacy (ORR and DCR) analysis in this study was performed based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Adverse events (AEs) were categorized and evaluated in accordance with the National Cancer Institute’s Common Terminology Criteria for Adverse Events, version 4.0.

Statistical analysis

Baseline characteristics, peripheral blood parameters, and treatment responses of the patients were summarized using median and interquartile ranges (IQRs) for continuous variables, while categorical variables were presented as frequencies and percentages. Data were analyzed using SPSS 25.0 and GraphPad Prism 9.0. The baseline characteristics of patients were evaluated using the chi-square test. Survival curves were constructed using the Kaplan-Meier estimator, and differences in survival were assessed using the log-rank test. Univariate and multivariate analyses were conducted using Cox proportional-hazards regression model. Logistic regression analysis was employed to evaluate the correlation between these parameters and treatment response. The discrepancy was found to be statistically significant at the P < 0.05 level.

Results

Baseline characteristics

Following a meticulous evaluation of 98 patients based on the predefined inclusion and exclusion criteria, we excluded 19 individuals who were unable to endure chemotherapy regimens, 8 with severe systemic or autoimmune disorders, 7 whose medical records were incomplete, and 4 lacking evaluable lesions for efficacy assessment (Fig. 1).

Fig. 1
figure 1

Flowchart of the study methodology.

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A total of 57 patients were enrolled in final analysis, comprising 35 males (61.4%) and 22 females (38.6%). The median age of the paticipants was 64 years, with an age range from 40 to 83 years. All patients included in this study were comfirmed to have primary pancreatic ductal adenocarcinoma. Baseline demographics and participant characteristics were well-balanced across the treatment groups (Table 1).

Table 1 Comparison of baseline characteristics between the two groups.
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Efficacy

At a median follow-up of 16.8 months, 57 progression-free survival and overall survival events were recorded. The median PFS for the overall population was 6.2 months. Specifically, the immunotherapy plus chemotherapy group achieved a median PFS of 7.3 months (95% CI 5.39–9.02) compared to 5.8 months (95% CI 3.69–7.91) for the chemotherapy-alone group. The combination immunotherapy group demonstrated a statistically significant improvement in PFS (hazard ratio [HR], 0.51; 95% CI, 0.29–0.87; P < 0.01). (Fig. 2). The overall median OS of all included subjects was 11.2 months. Notably, patients in the immunotherapy plus chemotherapy group achieved a median OS of 12 months (95% CI 9.21–14.80), whereas those receiving chemotherapy-alone had a median OS of 10.2 months (95% CI 8.03–12.37).

Notably, statistically disparities emerged between the two groups (hazard ratio [HR], 0.52; 95% CI, 0.26–1.00; P < 0.05) (Fig. 3).

Fig. 2
figure 2

Kaplan–Meier curves for PFS according to all patients (A), CT group and ICT group (B).

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Fig. 3
figure 3

Kaplan–Meier curves for OS according to all patients (A), CT group and ICT group (B).

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Based on the RECIST 1.1 evaluation criteria, no patients achieved a complete response (CR) in either group. In the chemotherapy-alone group, 5patients achieved partial response (PR) and 12 had stable disease (SD) resulting in an overall objective response rate (ORR) of 17.24% and a disease control rate (DCR) of 58.62%. In the immunotherapy plus chemotherapy group, 12 patients achieved PR and 10 had SD, leading to an ORR of 42.86% and a DCR of 78.57%. A statistically significant difference was observed in the ORR between the two groups (P < 0.05), whereas the difference in DCR did not reach statistical significance (Table 2).

Table 2 Summary of response for different treatment regimens.
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Univariate and multivariate analysis of ORR

To identify populations that could potentially benefit from immune combination therapy, we performed a univariate logistic regression analysis to investigate the factors influencing ORR. It was found that ECOG score, presence or absence of liver metastasis, treatment administration, baseline SOD level and SOD level after 8 weeks of treatment affected ORR. Subsequently, based on the results of the univariate analysis, we conducted a multivariate logistic regression analysis. The analysis results reveal that physical condition, presence or absence of liver metastasis, treatment administration, and SOD levels at 8 weeks post-treatment are the related factors influencing the patients’ attainment of objective response. For details, please refer to Table 3.

Table 3 Univariable and multivariable logistic regression models for ORR.
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Univariate and multivariate analysis of PFS and OS

Multivariate Cox regression analysis identified the following independent prognostic factors for PFS in patients with advanced PDAC: combination therapy (HR = 0.323, 95% CI 0.176–0.591, P < 0.001), ECOG performance status (HR = 4.415, 95% CI 1.889–10.318, P < 0.001), presence of liver metastasis (HR = 0.371, 95% CI 0.181–0.758, P = 0.007), reduction of CA199 at 8 weeks (HR = 0.390, 95% CI 0.191–0.798, P = 0.01), and increase in SOD levels at 8 weeks (HR = 0.284, 95% CI 0.147–0.548, P < 0.001) (Fig. 4).

Fig. 4
figure 4

Univariate and Multivariate Analysis of PFS.

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In the subgroup analysis of PFS, patients with an ECOG performance status score of 1 exhibited a median PFS of 5.6 months, which was notably shorter compared to those with a score of 0, who had a median PFS of 8.5 months. Patients with liver metastasis had a significantly shorter PFS of 5.7 months compared to 7.4 months for those without. Furthermore, patients who experienced a reduction in the tumor serum marker CA199 or an elevation in SOD levels after 8 weeks of treatment demonstrated significantly greater benefits in terms of PFS (Fig. 5).

Fig. 5
figure 5

Kaplan–Meier curves for PFS stratified by ECOG PS (A), presence of liver metastasis (B), serum SOD levels after 8 weeks of treatment (C), and CA199 levels after 8 weeks of treatment (D).

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Multivariate Cox regression analysis revealed that the following factors were independent associated with OS in patients with advanced PDAC: combination therapy (HR = 0.436, 95% CI 0.206–0.923, P = 0.03), presence of liver metastasis (HR = 0.267, 95% CI 0.114–0.625, P = 0.002), increase in SOD levels at 8 weeks (HR = 0.281, 95% CI 0.131–0.602, P = 0.001), and history of diabetes (HR = 2.745, 95% CI 1.217–6.190, P = 0.015)(Fig. 6).

Fig. 6
figure 6

Univariate and Multivariate Analysis of OS.

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In the subgroup analysis of OS, patients with liver metastasis had a significantly shorter OS of 9.2 months compared to 13.2 months for those without. Patients who experienced an elevation in SOD levels after 8 weeks of treatment demonstrated significantly greater benefits in terms of OS. Furthermore, patients with diabetes exhibited a significantly shorter median OS of 9.2 months compared to 12 months for those without diabetes. (Fig. 7).

Fig. 7
figure 7

Kaplan–Meier curves for OS stratified by presence of liver metastasis (A), serum SOD levels after 8 weeks of treatment (B), and history of diabetes (C).

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To identify patients who could benefit from immune combination therapy, we conducted a Cox regression analysis to evaluate the factors influencing PFS and OS in the ICT group. The multivariate Cox regression analysis revealed that basline SOD levels ≥ 154 KU/L (HR = 0.331, 95% CI 0.136–0.803, P = 0.014), a decrease in SOD levels at 8 weeks (HR = 4.410, 95% CI = 1.781–10.922, P = 0.001), and a history of diabetes (HR = 0.289, 95% CI = 0.117–0.713, P = 0.007) were independent prognostic factors significantly influencing PFS in patients with advanced PDAC receiving immunotherapy combined with chemotherapy (Table 4).

Table 4 Cox regression analysis of factors affecting PFS in patients with advanced PDAC in the immunotherapy combination group.
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Multivariate Cox regression analysis revealed that liver metastasis (HR = 0.075, 95% CI 0.015–0.368, P = 0.001), downregulation of SOD at 8 weeks (HR = 5.530, 95% CI 1.465–20.877, P = 0.012), and a history of diabetes (HR = 0.126, 95% CI 0.030–0.526, P = 0.004) are independent prognostic factors significantly impacting the OS of patients with advanced PDAC treated with immunotherapy combined with chemotherapy (Table 5).

Table 5 Cox regression analysis of factors affecting OS in patients with advanced PDAC in the immunotherapy combination group.
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Safety

There were no statistically significant differences between the two groups in terms of treatment-related adverse events at any grade (93.10% vs. 96.45%, P = 0.574), including hematological toxicity, nausea, vomiting, diarrhea, hepatic dysfunction, and fatigue (Table 6). Notably, there were no statistically significant differences in the incidence of grade 3 or higher treatment-related adverse events between the two groups (31.3% vs. 28.57%, P = 0.839) (Table 6). There were no fatalities attributable to the treatment in either cohort. Five patients in the immunotherapy combination group experienced immune-related adverse reactions (irAEs), specifically one case of immune-related pneumonia, three cases of immune-related rash, and one case of immune-related hypothyroidism. It is important to highlight that all immune-related adverse events (irAEs) were graded as level 1 or 2, with no instances of grade 3 or higher events (Table 6).

Table 6 Treatment-related adverse events in the two groups.
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Discussion

In this retrospective study, the combination of PD- 1 inhibitors with chemotherapy demonstrated significant improved PFS and OS compared to chemotherapy alone.

Furthermore, the objective response rate (ORR) in the PD- 1 combined chemotherapy group was significantly higher than that in the chemotherapy-only group. The two groups exhibited comparable safety profiles, with no emergence of new adverse events and no fatalities attributable to the treatment. This indicates that for patients with unresectable locally advanced or metastatic pancreatic cancer, the combination of immune checkpoint inhibitors (ICIs) with standard chemotherapy may provide superior treatment outcomes compared to standard chemotherapy alone. We acknowledge that this study is a retrospective real-world analysis with a limited sample size. Therefore, the findings presented herein require validation through well-designed, high-level clinical trials.

In recent years, immunotherapy has ushered in a new era for the treatment of solid tumors. Notably, the clinical application of immune checkpoint inhibitors (ICIs) has demonstrated remarkable efficacy across a wide range of malignant tumors21. However, the unique immunosuppressive tumor microenvironment of pancreatic cancer has posed significant challenges to the advancement of immunotherapy in this disease22. Despite extensive clinical trials assessing ICIs and other immunotherapies in pancreatic cancer, the majority of outcomes have been suboptimal, particularly in comparison to results observed in other malignancies. A substantial body of research has confirmed that pancreatic tumors exhibit relatively low infiltration by effector T cells, particularly in peritumoral tissues, and possess exceptionally strong immune evasion capabilities, rendering them among the “coldest” of tumors23,24,25. The efficacy of immune checkpoint inhibitors (ICIs) as monotherapy in the treatment of pancreatic cancer is suboptimal. Specifically, the objective response rate (ORR) for PD- 1, PD-L1, and CTLA- 4 monotherapies, as well as the combination of PD-L1 and CTLA- 4, ranges from 0 to 3%. Additionally, the median progression-free survival (PFS) and overall survival (OS) are only 1.5 months and 3.1 months, respectively26. A preclinical study demonstrated that gemcitabine can augment the immune response elicited by anti-PD- 1 antibodies, and the combination therapy proved beneficial in treating metastatic PDAC models27. Multiple clinical studies have demonstrated that anti-PD- 1/PD-L1 antibodies, when used in combination therapy, can significantly enhance the therapeutic efficacy for pancreatic cancer while maintaining a manageable safety profile17,28,29. The CISPD3 study is a single-center, randomized, open-label Phase III clinical trial comparing the efficacy and safety of sintilimab combined with modified FOLFIRINOX versus FOLFIRINOX alone as first-line or second-line treatment for patients with metastatic or recurrent PDAC. The results demonstrated that the median OS and PFS were comparable between the sintilimab plus chemotherapy group and the chemotherapy-alone group (10.9 vs. 10.8 months, 5.9 vs. 5.73 months, respectively). However, the ORR in the sintilimab plus chemotherapy group was 50%, which was significantly higher than the 23.9% observed in the chemotherapy-alone group30.The PRINCE5 study is a phase 2 randomized clinical trial that evaluates the efficacy of nivolumab and/or sotigalimab (a CD40 agonistic antibody) compared to historical controls treated with gemcitabine and nanoparticle albumin-bound paclitaxel in first-line patients with metastatic PDAC. In this randomized clinical trial, the survival rate of pancreatic cancer was increased by nearly 65% through the combination of immunotherapy and chemotherapy31. In this retrospective study, we also observed that the combination of PD- 1 inhibitors and chemotherapy could increase the ORR of patients compared with chemotherapy alone, and improve the median PFS and OS of patients. These results suggest that the combination of immunotherapy and chemotherapy holds potential clinical significance in pancreatic cancer.

Which groups of people can benefit from the combination of immunotherapy and chemotherapy is one of the directions for future exploration. We observed through multivariate Cox regression analysis that basline SOD levels ≥ 154 KU/L, a decrease in SOD levels at 8 weeks, and a history of diabetes were independent prognostic factors significantly influencing PFS in patients with advanced PDAC receiving immunotherapy combined with chemotherapy. Furthermore, liver metastasis, decreased SOD expression at 8 weeks, and a history of diabetes mellitus are independent prognostic factors that significantly influence the overall survival (OS) of patients with advanced pancreatic ductal adenocarcinoma (PDAC) treated with immunotherapy in combination with chemotherapy. Serum CA199 has been found to be an indicator of poor clinical prognosis for pancreatic cancer, but no correlation with the efficacy of combined immunotherapy has been discovered. CA199, a sialylated Lewis antigen produced by exocrine epithelial cells, is widely utilized as a biomarker for monitoring treatment efficacy and tumor recurrence in pancreatic cancer patients32. Hartwig et al.33found that elevated preoperative levels of CA199 are correlated with poorer prognosis in patients wiht pancreatic cancer. For patients undergoing treatment for metastatic disease, a reduction in CA199 within 8 weeks of therapy is significantly associated with extended OS34. SOD is a crucial antioxidant enzyme that plays a primary role in scavenging superoxide radicals, thereby mitigating oxidative stress. Furthermore, SOD is also involved in cellular signaling pathways and plays an important role in regulating cell survival35. Oxidative damage is intricately linked to various aspects of cancer biology, and SOD levels are considered indicative of the body’s antioxidant capacity.Consequently, SOD is regarded as a valuable tumor marker36. Studies have shown that elevated SOD levels are associated with increased invasiveness and metastasis rates in gastric and colorectal cancers, indicating its potential involvement in tumor suppression rather than suppression37,38. In contrast, O’Leary et al. reported a significant reduction in SOD mRNA expression in PDCA tissues relative to healthy pancreatic tissues39. The role of serum SOD as a prognostic indicator for malignant tumors warrants further investigation. Therefore, this study also investigated the correlation between SOD levels and the prognosis as well as therapeutic efficacy in pancreatic cancer patients.Our results demonstrate that patients with baseline SOD levels of 154 KU/L or higher exhibited significantly longer median PFS and OS compared to those with levels below 154 KU/L. Additionally, among patients with baseline SOD levels ≥ 154 (KU/L), those whose SOD levels continued to increase after 8 weeks of treatment exhibited significantly higher median PFS and median OS compared to those whose SOD levels decreased. Interestingly, in the subgroup analysis of patients receiving combined immunotherapy and chemotherapy, it was also observed that those who experienced a sustained increase in SOD levels at 8 weeks post-treatment achieved significantly longer PFS and OS from the combination therapy. Certainly, whether the serum SOD level can function as a reliable clinical prognostic marker for advanced PDAC and as a predictive indicator for the efficacy of immunotherapy combination treatment remains to be further substantiated through additional research.

An increasing body of evidence suggest that diabetes is a high-risk factor for the development of PADC. Studies indicate that diabetic patients have a 1.5 to 2-fold increased risk of developing pancreatic cancer. Studies show that diabetic patients have a 1.5 to 2-fold increases risk of developing pancreatic cancer40. Insulin resistance, hyperinsulinemia, hyperglycemia, inflammation, and alterations in β-cell function, including cell destruction, are considered key factors contributing to both burden of diabetes and the development of pancreatic cancer41,42. Compared to non-diabetic pancreatic cancer patients, diabetic patients exhibit markedly lower survival rates.Hyperglycemia promotes the proliferation of pancreatic cancer cells by upregulating the expression of epidermal growth factor (EGF) and subsequently activating the EGF receptor (EGFR)43. In this study, a total of 57 patients were included, with 24 (42.1%) having a history of diabetes. Survival analysis showed that patients without a history of diabetes had a significantly better median OS compared to those with a history of diabetes. However, no significant difference was observed in medianPFS. Furthermore, in the subgroup analysis, it was observed that patients with diabetes exhibited a diminished response to immune combination therapy relative to those without diabetes, as evidenced by shorter median PFS and OS.

Safety constitutes a paramount concern in this study, as it significantly influences the selection of treatment options for patients. Previous studies have shown that in patients with unresectable pancreatic cancer treated nivolumab combined with AG chemotherapy, the most common grade 3 or 4 adverse event was anemia, occurring at rate of 33%44. In another phase II trial, participants received a combination therapy consisting of AG chemotherapy and dual immune checkpoint inhibitors (durvalumab and tremelimumab). The results showed that the most frequent grade 3 or higher adverse events were hypoalbuminemia (45%), lipase abnormalities (45%), and anemia (36%)45. The main adverse reactions observed in this study were hematologic toxicity and gastrointestinal events, with fatigue being less frequent. The incidence of grade 3 or higher adverse reactions was relatively low, primarily manifesting as leukopenia, granulocytopenia, and thrombocytopenia.In the immune combination therapy group, the overall incidence of immune-related adverse reactions was relatively low, with no grade 3 or higher adverse events observed. Overall, the adverse reactions to the treatment were generally well-tolerated, demonstrating satisfactory safety profiles, and no fatalities attributable to adverse reactions were reported.

Although this study provides valuable clinical insights, it has several limitations. that should be acknowledged. Firstly, the sample size is limited, which may affect the generalizability of the findings. Secondly, this is a single-center retrospective study, potentially introducing selection bias. Moreover, Additionally, pre-treatment assessments of immune biomarkers such as PD-L1, TMB, and MSI were not conducted, thereby restricting our ability to conduct in-depth analyses.

In conclusion, this study retrospectively analyzed the efficacy and safety of immunotherapy combined with chemotherapy as a first-line treatment for advanced pancreatic cancer in a real-world setting. Additionally, it explored potential factors influencing prognosis and treatment outcomes. Our results indicate that the combination of immunotherapy and standard chemotherapy is superior to chemotherapy alone in terms of PFS and OS, and the adverse reactions are controllable. Preliminary findings indicate that patients without liver metastasis, without diabetes, or with elevated superoxide dismutase (SOD) levels following treatment may represent a more favorable population for combined immunotherapy. Future research should prioritize the identification of specific subgroups of pancreatic cancer patients who exhibit sensitivity to immunotherapy, thereby facilitating the development of more effective and targeted treatment strategies and enabling the selection of suitable patient populations. Multi-center randomized controlled trials are essential to further validate and generalize the findings of this study.