Small cell lung cancer (SCLC), accounting for around 13% of all lung cancers, often results in rapid tumor growth, early metastasis, and acquired therapeutic resistance. The POU class 2 homeobox 3 (POU2F3) is a master regulator of tuft cell identity and defines the SCLC-P subtype that lacks the neuroendocrine markers. Here, we have identified a previously uncharacterized protein, C11orf53, which is coexpressed with POU2F3 in both SCLC cell lines and patient samples. Mechanistically, C11orf53 directly interacts with POU2F3 and is recruited to chromatin by POU2F3. Depletion of C11orf53 reduced enhancer H3K27ac levels and chromatin accessibility, resulting in a reduction of POU2F3-dependent gene expression. On the basis of the molecular function of C11orf53, we renamed it as "POU Class 2 Homeobox Associating Factor 2" (POU2AF2). In summary, our study has identified a new coactivator of POU2F3 and sheds light on the therapeutic potential of targeting POU2AF2/POU2F3 heterodimer in human SCLC.