Exploiting CD36 as a self-facilitated endocytic receptor for PROTAC-mediated protein degradation: A new paradigm in...

The multifunctional scavenger receptor CD36 serves as a critical regulator in tumor progression by influencing processes such as fatty acid uptake, metabolic reprogramming, immune evasion, and metastasis. Conventional strategies to inhibit CD36, including use of monoclonal antibodies and small-molecule inhibitors, mainly impede the functional activity of this protein and are frequently hindered by compensatory mechanisms and emergence of resistance. The development of proteolysis-directed chimeras (PROTACs) represents a significant paradigm shift in therapy, transitioning from traditional protein inhibition to on-demand catalytic degradation of target proteins. This narrative review systematically examines the rationale, design, and therapeutic potential of applying PROTAC technology to induce the degradation of CD36 in cancer cells. Initially, we review the oncogenic implications of CD36 and the limitations of the existing inhibitors. Next, we outline the significant advantages associated with CD36 degradation compared to using the inhibitory strategy, such as overall functional elimination, avoidance of the compensatory mechanism, and possibility of prolonged effects. The review primarily focuses on addressing the strategic decision-making involved in the development of CD36-targeting PROTACs and includes a thorough discussion regarding the quality of the ligand (warhead) selection among known CD36 binders, selection of E3 ligase recruiters (e.g., cereblon [CRBN] and von Hippel Lindau [VHL]), and optimization of the linker. Subsequently, we indicate the opportunities of CD36 degraders in overcoming chemotherapy resistance, metastasis-activating cell growth, remodeling the immunosuppressive tumor microenvironment (TME), and enhancing the efficacy of radiotherapy. Lastly, we discuss major issues, including target selectivity, maximizing pharmacokinetics (PK), potential development of resistance, and risks associated with physiological functions of CD36. We also present future directions, including TME‑activated prodrugs, dual‑target PROTACs, and combination therapies.