Provided herein are oncolytic vaccinia viruses which have been modified to contain an exogenous nucleic acid that codes for a variant HMGB1 protein. Such vaccinia viruses modified to contain nucleic acid encoding variant HMGB1 and that express a variant HMGB1 or a fragment thereof can achieve a synergistic effect in combination with chemotherapy. Methods of using oncolytic vaccinia viruses modified to contain an exogenous nucleic acid that codes for a variant HMGB1 protein, in the treatment of various cancers, are also provided.