Targeting calreticulin (CALR) in tumors: Cellular mechanisms, structural insights and ligand development advances.

Calreticulin (CALR) is a multifunctional endoplasmic reticulum (ER)-resident chaperone protein that plays pivotal roles in regulating protein folding control, calcium ion homeostasis and immunogenic antigen presentation. Given its frequent overexpression in tumor cells, CALR significantly regulates tumor proliferation and therapeutic responses, positioning it as an attractive antitumor target. However, the exploration of CALR-targeting ligands remains largely unexplored in medicinal chemistry despite its established biological significance. This study provides comprehensive regulatory mechanisms of CALR across various cancer types and introduces research advances of wild-type and mutant CALR-binding compounds. By critically evaluating structural binding motifs, pharmacological efficacy and clinical limitations of existing ligands, our research offers new perspectives to guide future CALR-directed therapeutic discovery and optimization.