The latter approach with PD-(L)1 inhibitors has shown spectacular results in many indications, leading to first-line approvals of checkpoint inhibitor immunotherapy in renal cell carcinoma, non-small cell lung cancer, melanoma and others.4–6 Unfortunately, even in these highly promising settings, less than half of the patients have objective response to PD-(L)1 inhibitor therapy alone.7 For instance, only about one in three melanomas respond to PD-(L)1 inhibitor pembrolizumab.6 Intensive research is focused on identifying causes for intrinsic resistance to PD-(L)1 inhibitors. Here, CD274 is linked to hereditary clear cell renal cell carcinoma.