Activation of innate immune signaling in the tumor microenvironment is central to a successful anti-tumor immune response, and it is in large part mediated by cytosolic double-stranded DNA sensing. Here, Carozza et al. (2020b) report potent and selective inhibitors of ENPP1, a negative regulator of innate immune signaling, which are shown to potentiate anti-tumor immune responses.

Chemotherapeutic treatments are frequently impeded by the development of multidrug resistance (MDR). In this issue of Cell Chemical Biology, Wang et al. (2020) identify the natural product verucopeptin as having therapeutic potential toward MDR cancer cell types by targeting v-ATPase and mTORC1 signaling.

Cell permeable, small molecule inhibitors are powerful tools for interrogating kinase function and validating drug targets. In this issue of Cell Chemical Biology, Liu and colleagues (2020) describe the development of a toolkit containing a highly selective DCLK1 inhibitor and complementary DCLK1 mutants for interrogating DCLK1-dependent cellular processes.

Mammalian cryptochromes regulate sleep and metabolism as components of the circadian clock. In this issue of Cell Chemical Biology, Miller et al. (2020a) use phenotypic chemical screens to identify selective modulators of two cryptochrome isoforms. Binding specificity depends on conformational patterning of the ligand-binding pocket and a disordered C-terminal domain.

N-acyl amino acids are a class of biologically active lipids that control thermogenesis, and their biosynthesis is facilitated by PM20D1. In this issue of Cell Chemical Biology, Kim et al. (2020) identify a lipoprotein-albumin network in the blood that regulates physiological levels of N-acyl amino acids.

In this issue of Cell Chemical Biology, Hong et al. (2020) use in situ chemoenzymatic labeling to discover that fucosylation of the Wnt co-receptor LRP6 induces its endocytosis and downregulates Wnt/β-catenin signaling. Their findings reveal a glycosylation-based mechanism for regulating Wnt signaling that could be targeted in cancer.

K-RAS is known as the most frequently mutated oncogene. However, the development of conventional K-RAS inhibitors has been extremely challenging, with a mutation-specific inhibitor reaching clinical trials only recently. Targeted proteolysis has emerged as a new modality in drug discovery to tackle undruggable targets. Our laboratory has developed a system for targeted proteolysis using peptidic high-affinity