Clinical dose of enoxaparin enhances oncolytic virus M1 infection and antitumor efficacy in human bladder cancer

Cancer-associated thrombosis (CAT) is a major cause of morbidity and mortality in cancer patients, commonly treated with low-molecular-weight heparin (LMWH). LMWH is structurally similar to cell-surface heparan sulfate (HS), a key mediator of viral attachment, raising concerns that anticoagulation might interfere with oncolytic virotherapy. Here, we found that heparin directly binds oncolytic virus M1 (OVM). While high-dose enoxaparin inhibited viral infection, clinically relevant plasma concentrations (0.52–1.2 IU/mL) unexpectedly enhanced OVM infection and oncolysis in human bladder cancer cells. Mechanistically, enoxaparin at these concentrations facilitates viral attachment via HS proteoglycans (HSPGs). Crucially, this potentiation depends on the host innate immune landscape and is restricted to cells with attenuated interferon-α (IFN-α) responses. In vivo , clinically relevant enoxaparin significantly enhanced the antitumor efficacy of OVM without added toxicity, highlighting a novel and feasible strategy to potentiate oncolytic virotherapy using a standard anticoagulant in bladder cancer.