Targeted Molecular Construct for Bioorthogonal Theranostics of PD-L1-Expressing Cancer Cells

[Image: see text] Molecular targeting of tumor-overexpressed oncoproteins can improve the selectivity and tolerability of anticancer therapies. The immunoinhibitory membrane protein programmed death ligand 1 (PD-L1) is highly expressed on certain tumor types, which masks malignant cells from T cell recognition and creates an optimal environment for the cancer to thrive and spread. We report here a ligand-tetrazine conjugate (LTzC) armed with a PD-L1 small molecule inhibitor to selectively target PD-L1-expressing cancer cells and inhibit PD-L1 function and conjugated to a tetrazine module and a lipoyl group to incorporate bioorthogonal reactivities and an oxidative stress enhancer into the construct. By pairing LTzC with an imaging probe, we have established a “track-&-tag” system for selective labeling of PD-L1 both on and in living cells using click chemistry. We have further shown the specificity and versatility of LTzC by click-to-release activation of prodrugs and selective killing of PD-L1-expressing breast cancer cells, offering a new multimodal approach to “track-&-treat” malignant cells that are capable of evading the immune system.