Tsc2, a gene often associated with tuberous sclerosis complex, encodes the protein tuberin. It functions as a tumor suppressor and is a key regulator in the mammalian-target-of-rapamycin (mTOR) pathway, which controls cell growth, proliferation, and metabolism [2,4]. Genetic models, such as gene knockout mouse models, have been crucial for studying Tsc2's functions.

In a murine KrasG12D/Trp53-/-(KP) model, Tsc2 knockout promoted the transcriptional and membrane expression of PD-L1 in cell lines, and Tsc2-deficient tumors manifested an inflamed microenvironment. KP-Tsc2-KO tumors in syngeneic murine models showed a notable response to anti-PD-1 antibody treatment, indicating that loss of Tsc2 sensitizes non-small cell lung cancer to immune checkpoint blockade [1]. In another study, conditional gene knockout of Tsc2 in macrophages in an angiotensin II-induced mouse model showed that Tsc2 deficiency in macrophages aggravated the progression of aortic aneurysms, with up-regulation of proinflammatory cytokines and matrix metallopeptidase-9. This was associated with an up-regulation of Gpr68, and inhibition of Gpr68 abrogated the progression of aortic aneurysms caused by Tsc2 deficiency in macrophages [3].

In conclusion, Tsc2 is essential for regulating cell growth, proliferation, and immune-related responses through its role in the mTOR pathway. The use of Tsc2 knockout and conditional knockout mouse models has significantly enhanced our understanding of its role in diseases such as non-small cell lung cancer and aortic aneurysm formation, providing potential therapeutic targets for these diseases.