Targeting PIM kinases in cancer and inflammatory disorders: From mechanisms to clinical translation.

Proviral integration site for Moloney murine leukemia virus (PIM) kinase family (PIM1, PIM2, and PIM3) comprises constitutively active serine/threonine kinases that function as proto-oncogenic and immune-inflammatory signaling nodes. In cancer, PIM kinases promote tumor growth, therapeutic resistance, and immune microenvironment remodeling by phosphorylating substrates such as BCL2-associated agonist of cell death (BAD), Myc proto-oncogene protein (c-MYC), proline-rich AKT substrate of 40 kDa (PRAS40), and eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1)/eukaryotic translation initiation factor 4B (eIF4B), while integrating with Janus kinase/signal transducer and activator of transcription (JAK/STAT), phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin (PI3K/AKT/mTOR), nuclear factor kappa B (NF-κB), and NOD-like receptor family pyrin domain-containing 3 (NLRP3) signaling. In immune-inflammatory disorders, particularly through PIM1-dependent macrophage and T-cell regulation, these kinases amplify inflammatory signaling and contribute to pathological tissue remodeling. This review systematically summarizes the PIM kinase structural features, isoform-specific biology, signaling networks, disease-context dependency, inhibitor chemotypes, clinical development, and translational limitations of PIM-targeted therapy. We emphasize medicinal-chemistry strategies designed to exploit PIM dependency, including isoform-biased design, and emerging degrader-based approaches. PIM inhibitors have advanced from preclinical validation to clinical trials, but their clinical translation remains challenged by modest monotherapy activity, off-target toxicities, lack of validated predictive biomarkers, and paradoxical inhibitor-induced PIM stabilization. Therefore, future success will require the integration of rational combination therapies targeting PI3K/AKT/mTOR, JAK, proteasome, and immune-checkpoint pathways; structure-guided next-generation modalities, including isoform-selective inhibitors and targeted protein degraders; and biomarker-driven patient stratification to effectively translate PIM-targeted therapies into clinical practice.