Drugs that target immune checkpoints (ICPs) have become the most popular weapons in cancer immunotherapy; however, they are only beneficial for a small fraction of patients. Accumulating evidence suggests that the tumor immune microenvironment (TIME) plays a critical role in anti-cancer immunity. This study aimed to assess the potential merits and feasibility of combinational targeting ICPs and TIME in cancer immunotherapy. A total of 31 cancer type-specific datasets in TCGA were individually collected by the publicly available web servers for multiple bioinformatic analyses of ICPs and TIME factors. GEPIA was used to calculate the prognostic indexes, STRING was used to construct protein-protein interactions, cBioPortal was used for visualization and comparison of genetic alterations, and TISIDB was used to explore the correlation to tumor-infiltrating lymphocytes (TILs). Intriguingly, TIME factors were identified to have more global coverage and prognostic significance across multiple cancer types compared with ICPs, thus offering more general targetability in clinical therapy. Moreover, TIME factors showed interactive potential with ICPs, and genomic alteration of TIME factors coupled with that of ICPs, at least in pancreatic cancer. Furthermore, TIME factors were found to be significantly associated with TILs, including but not limited to pancreatic cancer. Finally, the clinical significance and translational potential of further combination therapies that incorporate both ICP inhibitors and TIME factor-targeted treatments were discussed. Together, TIME factors are promising immunotherapeutic targets, and a combination strategy of TIME factors-targeted therapies with ICP inhibitors may benefit more cancer patients in the future.