The treatment with OX-40 agonists promotes T cell activation and infiltration into tumors and it also prevents primary or acquired resistance to drugs targeting inhibitory checkpoints (e.g., PD-1, CTLA-4) as depicted in different preclinical cancer models (B16 melanoma, Lewis lung carcinoma, colon cancer and 4T-1 breast cancer). Here, TNFRSF4 is linked to cancer.