TPM3 (tropomyosin 3) is a critical regulator of muscle contraction that binds to actin filaments in both skeletal and smooth muscle cells. 1 In skeletal muscle, TPM3 functions as an indispensable regulator of muscle contraction in slow muscle fibers, working in association with the troponin complex to enable calcium-dependent regulation of striated muscle contraction. 1 TPM3 exists in multiple isoforms (TPM3α, TPM3ν, TPM3ξ, and TPM3ο) that are differentially expressed across tissues, with stronger expression in fetal heart and adult skeletal muscle compared to adult heart. 2 Beyond muscle contraction, TPM3 plays broader roles in actin filament organization and stabilization of the cytoskeleton in non-muscle cells. Mutations in TPM3 are associated with congenital myopathies 4A (autosomal dominant) and 4B (autosomal recessive), representing a class of genetic muscle diseases affecting actin-myosin interaction and myofibril force production. 3 Recent research has identified disease mechanisms by which TPM3 mutations lead to muscle dysfunction, though the precise mechanisms remain incompletely understood. 1 Additionally, TPM3 fusion proteins (TPM3-ALK, TPM3-NTRK1) have been identified in various malignancies including histiocytic neoplasms and renal cell carcinoma, where they function as oncogenic drivers responsive to targeted ALK inhibition. 456