Targeting intracellular immune regulatory molecules for cancer immunotherapy in solid tumors

Immune checkpoint inhibitors (ICIs) have transformed cancer therapy but remain limited by primary and acquired resistance, highlighting the need for novel immunotherapeutic strategies beyond cell-surface receptors. Intracellular immune regulators integrate signaling downstream of immune receptors and therefore represent attractive therapeutic targets capable of simultaneously modulating multiple immunosuppressive pathways. In this review, we summarize recent advances in therapeutics targeting intracellular immunoregulatory proteins that entered or advanced in clinical development between 2022 and 2026, with emphasis on representative targets, biological rationale, clinical development, and emerging therapeutic opportunities. We discuss membrane-proximal signaling regulators, intracellular signaling hubs, and innate immune mediators, including HPK1, DGKα/ζ, SHP2, CBL-b, PTPN1/2, JAK1, PI3Kγ/δ, MALT1, STING, and RIPK2. Current evidence indicates that intracellular regulators downstream of immune receptors warrant particular investigation because they integrate convergent signaling from multiple immune checkpoints and co-stimulatory receptors. Among these targets, HPK1 inhibitors have demonstrated preliminary monotherapy activity in selected patients, whereas the strongest clinical signals for SHP2 inhibition have been observed in combination with KRAS^G12C-targeted therapy and may reflect both tumor-cell-intrinsic and immune-mediated effects. Across multiple programs, rational combination strategies, biomarker-guided patient selection, optimized pharmacokinetic properties, and treatment sequencing appear more important than monotherapy. We further discuss major challenges, including incomplete understanding of target biology, limited druggability of certain intracellular proteins, and the need for improved translational strategies. Collectively, intracellular immunomodulators substantially expand the therapeutic landscape beyond conventional ICIs and may contribute to next-generation precision cancer immunotherapy.