Why Has PD-L1 Become a "Star Target" in Immunotherapy ? 

Structure: PD-L1 is an immunoglobulin superfamily transmembrane glycoprotein, and its core structure is divided into three parts: the extracellular IgV-like domain (the key region binding to PD-1 on the T cell surface), the IgC-like domain (maintaining protein conformational stability); the transmembrane region (maintaining the correct localization and orientation of PD-L1 on the cell membrane); the intracellular short tail region (mainly involved in protein internalization and turnover, and does not directly transmit immune suppression signals) (see Figure 1).

                                                                                                                                            Figure 1 Schematic diagram of PD-L1 structure[1]
                                                                                                                                              https://pubmed.ncbi.nlm.nih.gov/39080767/

Mechanism of Action: Under normal physiological conditions, PD-L1 is lowly expressed on immune cells (macrophages, dendritic cells) and epithelial cells, and its core function is to maintain immune homeostasis of the body; while tumor cells can abnormally overexpress PD-L1 through IFN-γ induction, gene mutation and other pathways. After binding to PD-1 on the T cell surface, it initiates inhibitory signals, leading to T cell exhaustion and immune escape (see Figure 2).

Figure 2 Mechanism of PD-L1-mediated immune escape
             Notably, the latest research published by Academician Bian Xiuwu's team in Cell Research in January 2026 revealed a novel immune escape function of PD-L1: PD-L1 itself has E3 ubiquitin ligase activity, which can induce β2m ubiquitination and degradation, reduce the level of MHC-I on the tumor cell surface, and impair the recognition ability of CD8+ T cells. This is also a novel intrinsic mechanism of PD-L1 inhibitor resistance[2]. The core role of PD-L1 inhibitors is to competitively bind to PD-L1 on the surface of tumor cells, block its interaction with PD-1, and reactivate T cell activity. Its advantages of broad spectrum, long-acting effect and safety have made it a core direction for global pharmaceutical companies to deploy.
 

Research Fields

            The research fields of PD-L1 (Programmed Death Ligand 1) are extensive. For example, in the development of tumor immunotherapy drugs, the development of PD-L1-targeted inhibitors, antibody drugs and novel therapeutic strategies, such as bispecific antibodies and antibody-drug conjugates (ADCs), to improve therapeutic effects and reduce side effects. Explore the combined application of PD-L1 inhibitors with other treatment methods (such as chemotherapy, radiotherapy, targeted therapy, cell therapy) to optimize treatment regimens. In autoimmune diseases, explore therapeutic targets, study the possibility of restoring immune balance by regulating PD-L1 expression or function, and develop PD-L1-targeted therapeutic drugs or strategies to provide new approaches for the treatment of autoimmune diseases. In addition, in infectious diseases, such as viral infections, study the role of PD-L1 in viral infections (such as hepatitis B virus, hepatitis C virus, HIV, COVID-19, etc.), analyze how viruses use PD-L1 to escape host immune attacks, and the potential application of PD-L1 inhibitors in antiviral therapy.
 

Drug Pipeline

                 Currently, PD-L1-targeted drug types mainly include monoclonal antibodies, bispecific/multispecific antibodies, antibody-drug conjugates (ADCs), small-molecule inhibitors and combined treatment regimens. Among them, PD-L1 monoclonal antibodies are the most numerous, but their proportion is decreasing year by year; PD-L1 bispecific/multispecific antibodies are growing the fastest and have become the mainstream of R&D; PD-L1 ADCs are in the early exploration stage; although the number of small-molecule PD-L1 inhibitors is small, they have the advantage of oral administration; and PD-L1 combined treatment regimens are widely used as the "base" of immunotherapy. The progress of various drug pipelines is as follows:
 

HLX-43: A novel antibody-drug conjugate (ADC) developed by Henlius Biotech, has become a potential candidate drug in the global tumor treatment field with its dual mechanism of action of "immune checkpoint blockade + cytotoxic killing". It has unique advantages especially in overcoming PD-1/PD-L1 inhibitor resistance and covering a wide range of tumor populations. Recently, Phase II clinical data in the treatment of recurrent/metastatic esophageal squamous cell carcinoma has been released. In addition, the drug has been granted orphan drug designation for thymic epithelial tumors (TETs) by the US FDA, and multiple clinical studies are advancing in various parts of the world.

 

Retlirafusp alfa Injection: Developed by Hengrui Medicine, Retlirafusp alfa is the world's first approved PD-L1/TGF-β bispecific antibody fusion protein. It was officially approved for marketing on January 16, 2026. Its indication is to be combined with fluoropyrimidine and platinum-based drugs for the first-line treatment of locally advanced unresectable, recurrent or metastatic gastric and gastroesophageal junction adenocarcinoma with PD-L1 positive (CPS≥1). It can simultaneously block the PD-L1 immune suppression and TGF-β tumor microenvironment suppression pathways, reshaping the pattern of precise immunotherapy for gastric cancer.

 

ABSK043: An oral small-molecule PD-L1 inhibitor developed by Hutchison MediPharma, announced the preliminary results of its Phase II clinical trial in combination with furmonertinib (a third-generation EGFR-TKI) for the treatment of NSCLC (non-small cell lung cancer) at the 2025 ESMO Asia Congress. The results showed that this "targeted-immune combination" regimen has good safety and tolerability. The regulatory authorities have agreed to carry out a study on its first-line treatment for treatment-naive EGFR-mutated and PD-L1-positive NSCLC patients, which is expected to fill the clinical gap of oral PD-L1 inhibitors.

 

Advantages of Nanobodies in PD-L1 drug R&D

              Nanobodies (single-domain antibodies, sdAbs) have become popular candidates for a new generation of immune checkpoint inhibitors due to their unique physicochemical properties. As heavy chain variable region fragments derived from camelids (approximately 15 kDa), nanobodies exhibit multiple advantages in drug R&D. Firstly, their small molecular weight endows them with excellent tissue penetration ability, and their tumor enrichment efficiency is significantly superior to that of traditional antibodies. For example, the PD-L1-targeted nanobody GS542 has shown potent blocking activity against the PD-1/PD-L1 interaction in in vitro experiments, and its inhibitory effect even exceeds that of the full-length antibody avelumab[3][4]. In addition, nanobodies lack the Fc domain, which can avoid side effects such as antibody-dependent cellular cytotoxicity (ADCC). Moreover, nanobodies also have excellent stability and can maintain structural integrity under extreme pH, repeated freeze-thaw and other conditions. This characteristic also significantly improves their applicability as drugs or diagnostic tools.

 

References: 

[1] Duan Z, Shi R, Gao B, Cai J. N-linked glycosylation of PD-L1/PD-1: an emerging target for cancer diagnosis and treatment. J Transl Med. 2024 Jul 30;22(1):705.

[2] Zhao, Q., Li, C., Zhang, M. et al. Tumor PD-L1 induces β2m ubiquitylation and degradation for cancer cell immune evasion. Cell Res 36, 38–50 (2026).

[3] Jean-Baptiste Marchand, Elodie Pintado, Marshall Dunlop, Christelle Remy, Patricia Kleinpeter, Shirley Shön, Fend Laetitia, Renée Brandely, Delphine Suhner, Eline Winter, Nathalie Silvestre, Claire Huguet, Peter Fitzgerald, Eric Quéméneur. Selection of an optimal anti-PD-L1 single domain antibody format for the vectorization into oncolytic vaccinia virus and the generation of bispecific immunomodulators. Cancer Res 2023;83(7_Suppl):Abstract nr 1885.

[4] Remy C, Pintado E, Dunlop M, Schön S, Kleinpeter P, Rozanes H, Fend L, Brandely R, Geist M, Suhner D, Winter E, Silvestre N, Huguet C, Fitzgerald P, Quéméneur E, Marchand JB. Design and selection of anti-PD-L1 single-domain antibody and tumor necrosis factor superfamily ligands for an optimal vectorization in an oncolytic virus. Front Bioeng Biotechnol. 2023 Nov 15;11:1247802.

 

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