Abrogating the immunoevasive role of the tumor immune microenvironment (TIME) represents a critical yet still elusive challenge in cancer treatment. Progress in this area has been hampered by both technological limitations and incomplete understanding of TIME-dependent immunoevasion mechanisms. We hypothesize that the immune-evasive role of TIME subpopulations-including regulatory T cells, cancer-associated fibroblasts, and tumor-associated macrophages-is critically mediated by hyperconnected Master Regulator Checkpoint (MRC) modules whose aberrant activity, as induced by paracrine signals, can be abrogated or modulated either genetically or pharmacologically. MRCs are primarily composed of transcription and co-transcription factors, acting downstream of surface receptors and signal transduction cascades to control the transcriptional identity and, ultimately, the phenotype of individual TIME subpopulations. Pharmacological inhibition of subpopulation-specific MRC proteins can thus help reprogram the TIME and potentially abrogate or modulate its immunosuppressive state. This paradigm shift, away from single ligand/receptor targeting, is supported by recent algorithmic, experimental, and clinical advances allowing systematic identification of MRCs and their pharmacological modulators using systems immunology-based approaches. Refocusing the deployment of existing tools and experimental methods that have proven successful in tumor cell contexts to identify and validate MRC-targeting agents capable of remodeling the immunosuppressive cell states of the tumor microenvironment can potentially pave the road to novel combination therapy synergizing with immune checkpoint inhibitors.