PKCθ: from T cell kinase to immunometabolic integrator.

Protein kinase C theta (PKCθ) has long been viewed as a core T cell signaling molecule. Recent work, however, reveals functions far beyond this classic role. In this review, we integrate recent evidence to redefine PKCθ as a pan-immune and immunometabolic integrator that controls not only T cell activation but also macrophage phagocytosis, natural killer cell (NK) function, and systemic metabolism. We analyze its paradoxical roles in cancer-where it drives some tumors but is lost in others-and summarize the evolution of therapeutic strategies beyond ATP-competitive inhibition, including allosteric modulation, proteolysis-targeting chimera degradation, and disruption of protein-protein interactions (PPIs). This aims to move the PKCθ field from fragmented descriptions toward mechanistic understanding and precision intervention.