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Id3, also known as inhibitor of DNA-binding/differentiation-3, is a transcription regulator that plays crucial roles in multiple biological processes. It is involved in pathways related to cell differentiation, immune response, and tumor regulation. In the immune system, it impacts T-cell development and macrophage polarization. In the context of tumors, it has potential tumor-suppressive functions [2,3,4]. Genetic models, such as gene knockout (KO) and conditional knockout (CKO) mouse models, are valuable tools for studying its functions.

In macrophages, ID3 deficiency experiments demonstrated that ID3 controls the balance between macrophage inhibitory and activating receptors. It endows Kupffer cells with the ability to phagocytose live tumor cells and orchestrate the recruitment, proliferation, and activation of natural killer and CD8 T lymphoid effector cells in the liver, restricting tumor growth [1]. In T-cell development, TCR-dependent upregulation of Id3 in a transient manner dislodges E proteins from their target sites during chromatin remodeling. After Id3 expression ceases, E proteins can bind to different target genes, influencing T-cell differentiation [2]. In lung cancer, ID3 acts as a direct target gene of p53. ID3 deficiency promoted the metastatic ability of lung cancer cells through regulating CDH1 transcription, while its ectopic expression restored E-cadherin expression [4]. In CD8+ T cells during tumorigenesis, ID3 deficiency significantly interrupted the maintenance of tumor-specific memory CD8+ T cells in draining lymph nodes, decreasing tumor-infiltrating CD8+ T cells and impairing tumor control [5].

In conclusion, Id3 is essential in immune-related cell differentiation and tumor regulation. Studies using KO/CKO mouse models have revealed its role in anti-tumor immune responses, T-cell development, and lung cancer metastasis. Understanding Id3's functions provides insights into the mechanisms of immune regulation and tumorigenesis, potentially offering new strategies for cancer treatment and immunomodulation.