DUX4 can be used as a biomarker for predicting a patient' s response to immunotherapy, and inhibition of DUX4 can be used in therapeutic methods for treating DUX4+ cancers. Accordingly, aspects of the disclosure relate to a method for treating cancer in a patient comprising administering a DUX4 inhibitor to the patient. Further aspects of the disclosure relate to a method for treating a DUX4+ cancer in a patient, the method comprising administering a checkpoint inhibitor to the patient. Other aspects relate to a composition comprising a DUX4 inhibitor and a checkpoint inhibitor.