Morecroft, Renee

e14545 Background: Durable antitumor immunity depends on the maintenance of stem-like CD8⁺ T cells capable of sustaining long-term effector responses. Oncolytic viruses (OVs) are potent immunomodulatory agents that reshape the tumor microenvironment and augment antitumor immunity. We hypothesized that platinum-based chemotherapy alters tumor-intrinsic type I interferon (IFN-I) signaling in a manner that can be functionally restored by OV therapy, thereby promoting the generation and persistence of stem-like CD8⁺ T cells. Methods: Tumor cells treated with platinum chemotherapy were evaluated in vitro for changes in IFN-I pathway activity, OV replication, and markers of immunogenic cell death (ICD). Syngeneic mouse tumor models were used to assess antitumor efficacy and immune remodeling following combination therapy. Tumor-infiltrating lymphocytes were analyzed by single-cell RNA sequencing and multiparameter flow cytometry to define CD8⁺ T-cell states and functional programs. Guided by these preclinical findings, a clinical trial combining XELOX, PD-1 blockade, and OV therapy was initiated (ChiCTR2500107607). Results: Platinum chemotherapy significantly suppressed tumor-intrinsic IFN-I signaling, while OV therapy restored antiviral responses, enhanced viral replication, and increased ICD in vitro. In vivo, the combination strategy resulted in superior tumor control and profound remodeling of the tumor immune microenvironment. The most pronounced immunologic effect was observed within the stem-like CD8⁺ T-cell compartment. Combination therapy induced a distinct population of TCF7⁺ ISG15^high NFATC1^low AP-1^low CD8⁺ T cells, characterized by restrained activation, enhanced persistence, and reduced propensity toward terminal exhaustion. In IRF7-deficient tumors, this stem-like CD8⁺ T-cell population failed to emerge and antitumor efficacy was significantly diminished, indicating that moderate tumor-intrinsic IFN-I signaling is required for this immune state. Conclusions: Tumor-intrinsic type I interferon signaling is a critical determinant of synergy between platinum chemotherapy and oncolytic virotherapy, enabling the maintenance of durable stem-like CD8⁺ T-cell immunity. These findings establish a mechanistic rationale for combining platinum chemotherapy, oncolytic viruses, and immune checkpoint blockade and support ongoing clinical translation. Clinical trial information: ChiCTR2500107607.

4235 Background: Malignant portal vein tumor thrombus (PVTT) arising from hepatic metastases is associated with poor prognosis, rapid hepatic decompensation, and limited effective local treatment options despite systemic therapy. In real-world practice, local treatment intensity is frequently adapted to disease burden and treatment response. We evaluated outcomes of a risk-adapted, step-up local treatment strategy using microwave ablation (MWA) alone or in combination with iodine-125 (I-125) seed implantation for patients with malignant PVTT. Methods: We retrospectively reviewed patients with hepatic metastases treated with MWA with or without I-125 seed implantation between 2023 and July 2025. In clinical practice, MWA alone was preferentially used for patients with relatively limited disease burden, while MWA plus I-125 was employed as an escalation strategy for patients with more advanced PVTT or disease progression following MWA alone. The primary endpoint was PVTT-directed local outcome, defined as portal vein patency and/or local control of tumor thrombus on follow-up imaging. Secondary endpoints included progression-free survival (PFS), overall survival (OS), hepatic function changes, and treatment-related toxicity. Survival analyses were considered exploratory. Results: A total of 73 patients were included, of whom 50 were treated with MWA alone and 23 with MWA plus I-125 seed implantation. Patients receiving MWA plus I-125 demonstrated more advanced disease characteristics, including universal presence of PVTT and higher disease stage, consistent with treatment escalation by disease severity. Among patients with PVTT, MWA plus I-125 achieved portal vein patency and/or local control in 65% at first follow-up imaging. Treatment-related toxicities were manageable, with no unexpected grade ≥3 adverse events attributable to I-125 implantation. Median PFS was 11.5 months in patients treated with MWA alone and 9.9 months in patients treated with MWA plus I-125, consistent with greater baseline disease burden in the latter group. Conclusions: MWA alone and MWA plus I-125 function as complementary components of a risk-adapted, step-up local treatment strategy for malignant PVTT from hepatic metastases. Escalation to MWA plus I-125 appears feasible in patients with advanced or refractory PVTT and demonstrates a potential signal for improved PVTT-directed local control and portal vein patency. Prospective studies focused on PVTT-specific endpoints are warranted.