Pancreatic cancer carries a dismal prognosis, with a 5-year survival rate of approximately 10%. Due to the lack of effective early screening methods, most patients present with locally advanced, vessel-involving tumors or distant metastases at diagnosis, rendering clinical management challenging. Under a multidisciplinary team (MDT) model, precision radiotherapy techniques have achieved multiple advances in recent years. Neoadjuvant or definitive stereotactic body radiotherapy (SBRT) combined with effective chemotherapy regimens can achieve high R0 resection rates and significantly prolong overall survival (OS). Magnetic resonance-guided radiotherapy (MRgRT) and stereotactic MR-guided adaptive radiotherapy (SMART) with online adaptive planning have further elevated the biological effective dose (BED) to >70 Gy while maintaining grade ≥3 toxicity rates below 3%. Clinical research has shown significant improvements in local control and delay to second-line treatment. Current challenges include defining the optimal radiotherapy window, individualizing target volumes and dose prescription, and integrating biomarker-guided immunotherapy or targeted combinations. Future efforts should establish evidence-based standardized combined radiotherapy regimens, investigate tumor microenvironment and DNA repair-related resistance mechanisms, and advance multimodal combinations with immune checkpoint inhibitors and targeted agents, to offer safer and more effective comprehensive treatment pathways for pancreatic cancer patients.

The liver is the most common metastatic site of pancreatic cancer, and patients with liver metastases have poor prognosis. In recent years, the application of systemic therapies and local treatment modalities has improved survival outcomes in this patient population. Currently, chemotherapy regimens based on gemcitabine and fluorouracil remain the primary therapeutic approach. Targeted therapies, such as PARP inhibitors (e.g., olaparib) and KRAS inhibitors, have shown promising efficacy in patients with specific genetic alterations. While immunotherapy demonstrates significant benefits in MSI-H/dMMR subtypes, its overall effectiveness remains limited, and combining immunotherapy with chemotherapy may represent a future direction for treatment optimization. In terms of local therapy, the “conversion therapy” model has enabled surgical resection in selected patients, significantly improving their prognosis. Additionally, local treatment modalities such as radiofrequency ablation, interventional therapy, and radiotherapy have enhanced local control rates in patients with liver metastases. Despite these advances, challenges remain, including limited treatment options, inconsistent definitions of oligometastasis, and a lack of consensus on surgical indications. Future efforts should focus on developing novel targeted therapies and immunocombination strategies, refining multidisciplinary management approaches, and ultimately transforming pancreatic cancer liver metastases into a chronic manageable condition.

Postoperative adjuvant therapy for pancreatic cancer has become the core component of comprehensive management. The mainstream regimens include gemcitabine monotherapy, gemcitabine combined with capecitabine, modified FOLFIRINOX, and gemcitabine combined with S-1. Full-dose and full-cycle chemotherapy is crucial to improving survival benefits for patients. Biomarkers such as circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), as well as technologies such as patient-derived organoid (PDO) drug sensitivity testing and artificial intelligence-assisted transcriptomic analysis, provide important support for precise and individualized adjuvant therapy. Adjuvant radiotherapy, targeted therapy, and immunotherapy show potential in high-risk patients. Future research should focus on head-to-head comparisons of multiple regimens and molecular stratification guidance to optimize combination therapy strategies and continuously enhance survival benefits for patients.

Locally advanced pancreatic cancer (LAPC), defined by tumor invasion of major peripancreatic vessels or critical structures, has traditionally been considered unresectable and is associated with a poor prognosis. Conversion therapy can downstage tumors in selected patients, enabling opportunities for radical (R0) resection and significantly improving survival. Preoperative selection of surgical candidates requires the comprehensive evaluation of contrast-enhanced computed tomography (CT), positron emission tomography-CT (PET-CT), changes in carbohydrate antigen 19-9 (CA19-9) levels, and patient performance status, and the application of the four-dimensional criteria of anatomy, biology, clinical condition, and duration of chemotherapy (the “ABCD” criteria). Surgical strategies include an artery-first approach with periadventitial dissection to enhance vascular control, with distal pancreatectomy and celiac axis resection (DP-CAR) or arterial reconstruction performed when necessary. Portal vein (PV) and superior mesenteric vein (SMV) resection and reconstruction follow the International Study Group of Pancreatic Surgery (ISGPS) classification, employing direct patch repair, end-to-end anastomosis, or interposition grafting as appropriate. Lymphadenectomy should encompass the Heidelberg triangle and level Ⅲ peripancreatic mesenteric nodal stations to reduce the risk of local recurrence. Given the high morbidity and mortality associated with these procedures, priority should be given to patients demonstrating favorable biological response and good tolerance, and surgeries should be performed by experienced multidisciplinary teams to balance radicality with safety.

Unresectable pancreatic cancer, including locally advanced pancreatic cancer (LAPC) and metastatic pancreatic cancer (MPC), is generally considered not suitable for surgical treatment, because surgery cannot improve the prognosis of patients. In recent years, with the development of preoperative treatment (such as chemotherapy and chemoradiotherapy) and surgical techniques (such as arterial, venous reconstruction, and autologous small intestine transplantation), the concept of conversion therapy provides opportunities for surgical resection for some unresectable pancreatic cancer patients. The median survival time of LAPC patients who underwent surgical resection after neoadjuvant therapy was 21.8 to 40.0 months, and the overall prognosis was significantly better than that of the non-surgical group. MPC patients can also be converted to surgical resection after effective systemic treatment. Nevertheless, the conversion therapy of unresectable pancreatic cancer still faces many challenges, including the low effective rate of neoadjuvant treatment, high early recurrence rate, and no unified and effective patient screening and prediction criteria. In the future, with the rapid development of precision medicine and new treatment methods, through multidisciplinary cooperation and continuous clinical research, conversion therapy is expected to bring survival benefits to more patients with unresectable pancreatic cancer.

Pancreatic cancer is characterized by high malignancy and a lack of effective early diagnostic tools, resulting in most patients being diagnosed at an unresectable advanced stage, with a 5-year survival rate of approximately 13%. Traditional gemcitabine-based chemotherapy and single-targeted therapies (e.g., EGFR inhibitors, KRAS inhibitors) have shown limited efficacy, primarily due to the dense collagenous stroma and cancer-associated fibroblasts forming a drug-resistant barrier, as well as the high degree of tumor heterogeneity. Systems biology enables precise molecular subtyping through the integration of multi-omics data and, when combined with network pharmacology, facilitates the identification of multi-target combination strategies aimed at overcoming drug resistance and the immunosuppressive tumor microenvironment. Digital twin platforms can simulate tumor progression and drug responses in individual patients, thus guiding personalized therapeutic optimization. Clinical trials have demonstrated that KRAS G12D inhibitor MRTX1133, KRAS G12C inhibitors adagrasib and sotorasib, and the PARP inhibitor olaparib exhibit synergistic antitumor activity in specific molecular contexts. Multi-target combination strategies, in conjunction with artificial intelligence and real-time dynamic monitoring, hold promises for improving treatment efficacy and clinical outcomes in pancreatic cancer.

Pancreatic cancer is among the most lethal malignancies of the digestive system, with an overall 5-year survival rate of only 13%. In recent years, advances in tumor molecular biology have shifted therapeutic strategies from a “one-size-fits-all” approach to molecular subtype-based, targeted, and personalized therapies. Concurrently, the widespread implementation of multidisciplinary team (MDT) collaboration and full-cycle patient management has optimized the comprehensive treatment paradigm, aiming to balance undertreatment and overtreatment. However, the high heterogeneity of pancreatic cancer, limited availability of targeted approaches for key driver genes, intrinsic and acquired resistance mechanisms, and the immunosuppressive tumor microenvironment continue to significantly hinder the advancement of precision molecular classification and individualized treatment, leading to no substantial improvement in patient prognosis to date and enormous challenges in clinical diagnosis and treatment. Current research indicates correlations between molecular subtypes (including classical, basal-like, quasi-mesenchymal, and squamous) and clinical phenotypes. Liquid biopsy technologies—such as circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), and exosomes—are being explored for early diagnosis and real-time disease monitoring. In targeted therapy, research is centered on KRAS and resistance mechanisms. Immunotherapy must overcome the challenges of low immunogenicity and an immunosuppressive tumor microenvironment, with various combination strategies undergoing clinical investigation. Artificial intelligence (AI) and big data are expected to enhance diagnostic imaging, molecular subtyping, and intraoperative navigation. Future directions should focus on strengthening interdisciplinary collaboration and integrating molecular classification, targeted and immunotherapeutic strategies, and AI technology to realize precision, comprehensive treatment for pancreatic cancer.

pancreatic cancer is characterized by a profoundly immunosuppressive tumor microenvironment, rendering it a prototypical“cold tumor”and limiting the efficacy of immune checkpoint inhibitors (ICIs) as monotherapy. In recent years, various combination strategies have been proposed to enhance the therapeutic response to ICIs, including their integration with chemotherapy, radiotherapy, targeted therapy, oncolytic viruses, STING agonists, personalized vaccines, and chimeric antigen receptor (CAR) T-cell therapies. These combinatorial approaches aim to induce immunogenic cell death, activate interferon signaling pathways, remodel the tumor microenvironment, and enhance T cell function, thereby increasing the immunogenicity of pancreatic cancer. Although preliminary studies have shown that such combinations can yield clinical benefits, challenges remain complex, including increased immune-related toxicity, high interpatient heterogeneity, the lack of predictive biomarkers, and complex mechanisms of resistance. Future efforts should focus on refining patient selection, elucidating underlying biological mechanisms, and conducting robust clinical trials to facilitate the transition of immunotherapy for pancreatic cancer from experimental exploration to standardized clinical application, particularly in advanced-stage and adjuvant treatment settings.

Tumor vaccines activate T cell-mediated immunity by targeting pancreatic cancer-associated antigens or neoantigens and have become a research focus. Current strategies include mRNA vaccines, dendritic cell (DC) vaccines, peptide vaccines, and whole-cell vaccines. Personalized mRNA vaccines can rapidly encode patient-specific neoantigens, inducing durable CD8⁺ T cell responses; fixed-target mRNA vaccines directed against KRAS mutations have demonstrated favorable immunogenicity. DC vaccines load tumor antigens to activate both CD4⁺ and CD8⁺ T cells; when combined with chemotherapy or immune checkpoint inhibitors, they can modulate the tumor microenvironment and enable partial conversion to resectable disease. Peptide vaccines targeting antigens such as MUC1 and WT1 have shown limited efficacy; whole-cell vaccines (e.g., GVAX), in combination with immune checkpoint inhibition or stereotactic radiotherapy, hold promise for enhanced antitumor activity. Efficacy assessment requires integration of overall survival, progression-free survival, recurrence-free survival, and immunological biomarkers. The immunosuppressive tumor microenvironment and low response rates in pancreatic cancer remain major challenges. Future directions should optimize antigen selection, adjuvants, and combination regimens, while leveraging artificial intelligence to improve neoantigen prediction, thereby providing new avenues for clinical application of tumor vaccines in pancreatic cancer.