Osr2, or odd-skipped related 2, encodes a zinc-finger containing transcription factor. It plays crucial roles in multiple biological processes. In the extracellular matrix (ECM)-related cancer context, it acts as a biomechanical checkpoint, integrating biomechanical signaling to facilitate terminal exhaustion of tumor-reactive CD8+ T cells [1]. It is also involved in skeletal development, osteoblast differentiation, and chondrocyte-related cartilage homeostasis [2,3]. Additionally, it is essential in craniofacial, limb, kidney, tooth, and palate development [4-7].

In gene-targeted mouse models, depletion of Osr2 alleviates exhaustion of tumor-specific CD8+ T cells or CAR-T cells, indicating its role in promoting CD8+ T cell exhaustion in solid tumors [1]. In tooth development, deletion of Osr2 in Runx2 mutant mice partially rescues tooth development, suggesting its inhibitory role in normal tooth development pathways [4]. In palate development, a targeted null mutation in Osr2 impairs palatal shelf growth, causing cleft palate due to reduced palatal mesenchyme proliferation [5].

In conclusion, Osr2 is a key regulator in multiple biological processes. Its study using KO/CKO mouse models has revealed its importance in cancer immunotherapy-related T cell exhaustion, as well as in skeletal and organ development. Understanding Osr2's functions provides insights into disease mechanisms and potential treatment strategies in these areas.