Consensus, debate, and prospective on pancreatic cancer treatments

Abstract

Pancreatic cancer remains one of the most aggressive solid tumors. As a systemic disease, despite the improvement of multi-modality treatment strategies, the prognosis of pancreatic cancer was not improved dramatically. For resectable or borderline resectable patients, the surgical strategy centered on improving R0 resection rate is consensus; however, the role of neoadjuvant therapy in resectable patients and the optimal neoadjuvant therapy of chemotherapy with or without radiotherapy in borderline resectable patients were debated. Postoperative adjuvant chemotherapy of gemcitabine/capecitabine or mFOLFIRINOX is recommended regardless of the margin status. Chemotherapy as the first-line treatment strategy for advanced or metastatic patients included FOLFIRINOX, gemcitabine/nab-paclitaxel, or NALIRIFOX regimens whereas 5-FU plus liposomal irinotecan was the only standard of care second-line therapy. Immunotherapy is an innovative therapy although anti-PD-1 antibody is currently the only agent approved by for MSI-H, dMMR, or TMB-high solid tumors, which represent a very small subset of pancreatic cancers. Combination strategies to increase the immunogenicity and to overcome the immunosuppressive tumor microenvironment may sensitize pancreatic cancer to immunotherapy. Targeted therapies represented by PARP and KRAS inhibitors are also under investigation, showing benefits in improving progression-free survival and objective response rate. This review discusses the current treatment modalities and highlights innovative therapies for pancreatic cancer.

Keywords: Chemotherapy; Immunotherapy; Pancreatic cancer; Radiotherapy; Surgery; Targeted therapy; Tumor microenvironment.

Fig. 1

Timeline for pancreatic cancer treatment progression. Initial research demonstrated the efficacy of gemcitabine (Gem) as both adjuvant therapy for resectable pancreatic cancer and systemic treatment for advanced disease. Over the past decade, significant advancements have been made in chemotherapy options for pancreatic cancer, including the introduction of FOLFIRINOX (oxaliplatin, irinotecan, leucovorin, and fluorouracil), gemcitabine plus nab-paclitaxel (Gem + nab-P), S-1, liposomal irinotecan (Nal-IRI), gemcitabine plus capecitabine (Gem + Cap), modified FOLFIRINOX (mFOLFIRINOX), and NALIRIFOX (liposomal irinotecan, oxaliplatin, leucovorin, and fluorouracil). Immunotherapy has also made strides, with pembrolizumab, which targets the PD-1/PD-L1 immune checkpoint pathway, showing improved outcomes in MSI-H/dMMR and TMB-H solid tumors. Erlotinib, an EGFR-targeting agent, showed slight improvement when combined with Gem compared to Gem alone. Recent clinical investigations have highlighted the efficacy of PARP inhibitors such as olaparib in significantly prolonging survival for patients with germline BRCA-mutated pancreatic cancer, leading to FDA approval for maintenance treatment in cases with non-progressing disease following at least 16 weeks of first-line platinum-based chemotherapy. Moreover, targeted therapies such as larotrectinib and entrectinib for NTRK fusion-positive solid tumors, dabrafenib and trametinib for solid tumors with BRAF^V600E mutations, and selpercatinib for RET fusion-positive solid tumors have received FDA approval. In the figure, red font denotes treatment strategies that demonstrated superior outcomes in corresponding randomized controlled trials, while orange font highlights the specific genetic alterations or subtypes targeted by the therapies

Fig. 2

Immunomodulatory strategies for reprogramming the tumor microenvironment to enhance antitumor immunity. The pancreatic tumor microenvironment (TME) is characterized by an abundance of immunosuppressive cells, such as tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), and cancer-associated fibroblasts (CAFs), all embedded within a dense fibrotic stroma. Targeting these immunosuppressive myeloid cells involves inhibiting pathways such as CSF-1R, CCL2/CCR2, CXCR1/2, CXCL8, and CXCL12/CXCR4, while activating CD40 and CD11b to prevent their migration and reduce immunosuppression. Innate immune responses are stimulated through small molecule innate agonists or radiation to create a proinflammatory microenvironment and boost antitumor immunity. Cancer vaccines—including whole-cell, antigen-specific, and neoantigen-based vaccines—activate dendritic cells (DCs) to present tumor antigens, promoting targeted immune responses. Cell therapies, including TILs, CAR-T, CAR-NK, and TCR-engineered T-cell therapies, are employed to enhance cytotoxic activity against tumor cells by targeting specific antigens such as HER2, CEA, EGFR, mesothelin, and mutant KRAS. Immune checkpoint inhibitors targeting PD-1/PD-L1, CTLA-4, and other emerging checkpoints like LAG-3, TIM-3, and TIGIT are utilized to unleash T cell-mediated responses, overcoming immune evasion within the TME. Additionally, stroma modulation is achieved through the use of MMP inhibitors, TGF-β inhibitors, FAP-targeting agents, and FAK inhibitors, which disrupt the tumor-supportive environment. These strategies collectively aim to shift the TME from an immunosuppressive to an immunostimulatory state, augmenting therapeutic outcomes in pancreatic cancer, particularly when combined with chemotherapy and/or targeted therapy

Fig. 3

Therapeutic strategies targeting KRAS mutations in pancreatic cancer. KRAS, a GTPase, transitions between an inactive GDP-bound state and an active GTP-bound state, driving downstream signaling pathways that promote cell proliferation and survival, such as the PI3K/AKT/mTOR and RAF/MEK/ERK pathways. Therapeutic strategies targeting KRAS aim to prevent its activation, disrupt its signaling, or indirectly inhibit the KRAS pathway upstream. KRAS inhibitors can directly bind to either the GDP-bound or GTP-bound state of KRAS, disrupting further signaling. Specific inhibitors for KRAS^G12C (e.g., Sotorasib, Adagrasib) and KRAS^G12D (e.g., MRTX1133, ASP3082) mutations target specific isoforms of mutated KRAS, while pan-RAS inhibitors (e.g., RMC-6236) offer a broader approach by targeting multiple RAS isoforms. Indirect inhibition of the KRAS pathway is being explored through upstream inhibitors, such as SHP2 and SOS1 inhibitors. Downstream inhibitors disrupt key signaling pathways activated by KRAS, with examples including PI3K/AKT inhibitors (Rigosertib, Inavolisib), mTOR inhibitors (Everolimus), and RAF/MEK inhibitors (Avutometinib). Additionally, novel KRAS-directed delivery routes, including vaccines targeting specific KRAS mutations (e.g., ELI-002), CAR-T cell therapies, and exosomes loaded with siRNA targeting the KRAS^G12D mutation, are also under investigation