CDK4 and neoplasm: In this regard, some studies have found that pharmacological inhibition of canonical downstream targets of p16, namely CDK4/6, leads to an induction of SASP factors, recruitment of antitumor immune cells, and senescence [95–98], suggesting that p16-loss-mediated regulation of SASP expression and the tumor immune microenvironment may be due to non-canonical (RB-independent) mechanisms.