Abstract: Although cancer immunotherapy has improved the prognosis of various malignancies, its clinical efficacy remains limited by intrinsic tumor survival programs and the immunosuppressive tumor microenvironment (TME). Recent studies indicate that the heterogeneity of immunotherapy responses is influenced not only by immune checkpoint expression and antigen burden, but also by the coordinated regulation of intracellular signaling, metabolic homeostasis, and cell fate programs. The tumor necrosis factor-alpha-induced protein 8 (TNFAIP8/TIPE) family comprises highly conserved cytoplasmic proteins that function as both lipid messengers and signaling regulators, acting as “intracellular immune rheostats” in innate and adaptive immunity. This review systematically integrates the context-dependent roles of TIPE family members across various therapeutic modalities, including immune checkpoint blockade (ICB), oncolytic viruses (OV), adoptive cell therapy (ACT), antibody drugs, and cancer vaccines. Based on current research that the TIPE family systematically shapes the threshold and persistence of immune responses by synergistically regulating lipid pathways (e.g., the PI3K-AKT axis), inflammatory sensing signals, and cytoskeletal dynamics. We discuss potential translational strategies targeting the TIPE signaling axis to overcome immunotherapeutic resistance, providing a theoretical framework for developing next-generation precision immunotherapies.