PDCD1 and cancer: To summarize the interactive roles of STIE and TIME and clarify their impacts on tumor progression and therapeutic efficacy, we elected to address the following challenges associated with PD-1 inhibitor treatment: (1) an overall low response rate and the heterogeneity of therapeutic efficacy of immunotherapy, (2) the communications between STIE and TIME that establish the environment for cancer metastasis (e.g., brain metastasis), (3) hyperprogressive disease, and (4) treatment-related adverse effects.