Challenges Coexist with Opportunities: Spatial Heterogeneity Expression of PD-L1 in Cancer Therapy

Cancer immunotherapy using anti-programmed death-ligand 1 (PD-L1) antibodies has been used in various clinical applications and achieved certain results. However, such limitations as autoimmunity, tumor hyperprogression, and overall low patient response rate impede its further clinical application. Mounting evidence has revealed that PD-L1 is not only present in tumor cell membrane but also in cytoplasm, exosome, or even nucleus. Among these, the dynamic and spatial heterogeneous expression of PD-L1 in tumors is mainly responsible for the unsatisfactory efficacy of PD-L1 antibodies. Hence, numerous studies focus on inhibiting or degrading PD-L1 to improve immune response, while a comprehensive understanding of the molecular mechanisms underlying spatial heterogeneity of PD-L1 can fundamentally transform the current status of PD-L1 antibodies in clinical development. Herein, the concept of spatial heterogeneous expression of PD-L1 is creatively introduced, encompassing the structure and biological functions of various kinds of PD-L1 (including mPD-L1, cPD-L1, nPD-L1, and exoPD-L1). Then an in-depth analysis of the regulatory mechanisms and potential therapeutic targets of PD-L1 is provided, seeking to offer a solid basis for future investigation. Moreover, the current status of agents is summarized, especially small molecular modulators development directed at these new targets, offering a novel perspective on potential PD-L1 therapeutics strategies. In terms of PD-L1's diverse expression, the concept of "spatial heterogeneity expression" is proposed to enhance comprehension of its tumor immune/non-immune regulatory mechanism. Additionally, the structure, function, and regulatory mechanisms of PD-L1 in various subcellular locations are summarized. Furthermore, potential modulators, including degraders, down regulators, and covalent inhibitors, are identified, providing valuable insights for future endeavors in drug development, delivery, and clinical therapy.image