Birc2, also known as baculoviral IAP repeat-containing 2, is an inhibitor of apoptosis protein that regulates fundamental cell death and survival signaling pathways. It is involved in pathways like the non-canonical NFκB signaling pathway [2]. Birc2 has been shown to be of great biological importance in processes such as immune evasion, cell proliferation, and apoptotic escape in various diseases [2,3]. Genetic models, especially gene knockout (KO) and conditional knockout (CKO) mouse models, have been valuable for studying its functions.

Knockdown of Birc2 in mouse melanoma or breast cancer cells increased the expression of chemokine CXCL9, enhanced the number of intratumoral activated CD8+ T cells and natural killer cells, and thus impaired tumor growth. This also significantly increased the sensitivity of these tumors to anti-CTLA4 and/or anti-PD1 immune checkpoint blockade (ICB), demonstrating its role in anti-cancer immunity and immunotherapy efficacy [1]. In hepatocellular carcinoma (HCC), knockdown of Birc2 using shRNA or small-molecule inhibitors increased the sensitivity of HCC cells to immune killing and improved the function of T cells. Birc2 interacted with and promoted the ubiquitination-dependent degradation of NFκB-inducing kinase (NIK), leading to inactivation of the non-canonical NFκB signaling pathway, decreased major histocompatibility complex class I (MHC-I) expression, and protection of HCC cells from T cell-mediated cytotoxicity [2]. In head-and-neck squamous cell carcinomas (HNSCCs) in Fanconi anemia (FA) patients, amplification of 11q22.2 led to strong overexpression of Birc2, and the drug AZD5582, an inhibitor of Birc2-3, selectively killed FA tumor cells overexpressing Birc2-3 [4].

In conclusion, Birc2 plays a crucial role in immune evasion, tumor cell survival, and apoptotic escape. Studies using KO/CKO mouse models have revealed its significance in cancer immunotherapy resistance, especially in melanoma, breast cancer, and HCC. Additionally, in FA-associated HNSCCs, Birc2 overexpression due to gene amplification may provide a potential druggable target. Understanding Birc2's functions through these model-based studies helps in developing novel strategies for treating related diseases.

References:

1. Samanta, Debangshu, Huang, Tina Yi-Ting, Shah, Rima, Pan, Fan, Semenza, Gregg L. . BIRC2 Expression Impairs Anti-Cancer Immunity and Immunotherapy Efficacy. In Cell reports, 32, 108073. doi:10.1016/j.celrep.2020.108073. https://pubmed.ncbi.nlm.nih.gov/32846130/

2. Fu, Lingyi, Li, Shuo, Mei, Jie, Huang, Yuhua, Yun, Jingping. 2025. BIRC2 blockade facilitates immunotherapy of hepatocellular carcinoma. In Molecular cancer, 24, 113. doi:10.1186/s12943-025-02319-5. https://pubmed.ncbi.nlm.nih.gov/40223121/

3. Zhang, Shi-Long, Zhang, Shen-Jie, Li, Lian, Chen, Teng-Xiang, Zuo, Shi. 2024. NAP1L1 regulates BIRC2 ubiquitination modification via E3 ubiquitin ligase UBR4 and hence determines hepatocellular carcinoma progression. In Cell death discovery, 10, 154. doi:10.1038/s41420-024-01927-2. https://pubmed.ncbi.nlm.nih.gov/38538582/

4. Roohollahi, Khashayar, de Jong, Yvonne, Pai, Govind, Wells, Susanne I, Dorsman, Josephine. 2022. BIRC2-BIRC3 amplification: a potentially druggable feature of a subset of head and neck cancers in patients with Fanconi anemia. In Scientific reports, 12, 45. doi:10.1038/s41598-021-04042-9. https://pubmed.ncbi.nlm.nih.gov/34997070/