溶瘤病毒-化疗联合可改善对PDAC生长和扩散的控制

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest solid tumors. Its progression is driven by KRAS-dependent signaling, a dense desmoplastic stroma, early metastatic spread, and an immunologically ‘cold' tumor microenvironment (TME). Therapies that combine direct cytotoxic activity with TME reprogramming may improve treatment response. Oncolytic virotherapy offers such a dual mechanism.We hypothesize that a genetically engineered herpes simplex virus (HSV-1) strain, HSV-1(VC2), engineered to express murine GM-CSF, can synergize with gemcitabine by modulating tumor-intrinsic signaling and initiating early steps toward a more immune-responsive TME. In vitro studies using murine KRAS G12D TP53 R172H Cre (KPC) cells demonstrated a strong synergistic interaction between the proposed oncolytic virus (oV) and gemcitabine, as supported by ZIP synergy modeling. qPCR analysis showed that gemcitabine increased EMT-associated transcripts (TGF-beta, fibronectin, TAZ) as well as pro-survival/pro-migratory transcripts (CAV1, AKT, CTNNB1, PI3K). The oV alone activated STING-associated innate immune pathways. The combination treatment suppressed gemcitabine-induced EMT and proliferative signaling while maintaining antiviral and immunostimulatory gene expression, indicating coordinated transcriptional modulation consistent with enhanced cytotoxic and immunogenic activity.To evaluate in vivo relevance, we used an orthotopic immunocompetent PDAC model in which 10 4 KPC cells were surgically implanted into the pancreas of WT C57BL/6 mice. This model reflects PDAC growth kinetics and metastatic behavior. In preliminary studies, oncolytic virotherapy alone did not reduce tumor size but markedly reduced liver metastasis, with 1 of 4 mice showing liver involvement compared to 4 of 4 in the control group at day 38. In another study, the same OV application schedule (administered on days 10 and 24 after tumor implantation) was used together with gemcitabine (given weekly starting on day 11 at 100 mg/kg). This combination further decreased primary tumor burden compared with either monotherapy at the 38-day endpoint (n=8 mice/group). A Panc-1 xenograft model showed similar patterns in primary tumor reduction and metastatic spread.Ongoing work includes flow cytometry, targeted transcriptomics, and proteomic profiling to define immune and molecular contributors to synergy. Additionally, in vitro studies using human PDAC and pancreatic stellate cell 3D co-cultures, as well as human PDAC organoids, are in progress. Together, these findings position HSV-1(VC2) GM-CSF as a clinically relevant partner for gemcitabine and a potential strategy to improve PDAC responsiveness through both cytotoxic and immune-mediated effects.