Notably, tumor-intrinsic checkpoint molecules such as PD-L1 can be regulated independently of immune infiltration, often upregulated through oncogenic or stress-response pathways such as p62–NRF2–mTORC1 signaling, even when PD-1 and CTLA-4 expression decline in immune-cold contexts [9, 88, 100]. Here, CD274 is linked to neoplasm.