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Background: The distribution of human leukocyte antigen-G (HLA-G) is limited in physiological situations. Functionally, HLA-G is an important immunotolerant that comprehensively suppresses the biological functions of immune cells through HLA-G/receptor interactions. Abnormal induced expression of HLA-G has been detected in various types of cancer, and different degrees of HLA-G expressions are closely related to rapid tumor progression and/or worse clinical outcomes. Currently, HLA-G-based signaling is established as an immune checkpoint, and clinical trials of HLA-G-targeted immunotherapy for advanced solid cancers were launched in 2020. In this review, we focused on the important developments and achievements related to HLA-G as a novel immune checkpoint and the challenges that remain to be addressed for solid cancer immunotherapy. Methods: PubMed was comprehensively searched to identify relevant literature written in English and published on or before October 1, 2021. The keywords used for the search were HLA-G, cancer, malignancy, tumor, and prognosis combined with “and”/ “or.” Results: Cancer-restricted abnormally induced HLA-G expression is detected in most types of malignancies, while HLA-G expression is absent in non-tumorous adjacent tissues. By interacting with immune receptors such as immunoglobulin-like transcripts (ILT)-2, ILT-4, and killer cell immunoglobulin-like receptor (KIR)2DL4, HLA-G inhibits biological functions of different types of immune cells, favoring cancer cell immune evasion and disease progression. Induced HLA-G in cancer cells has been well acknowledged to be with enhanced tumor cell metastasis, advanced disease stage, and worse prognosis. The HLA-G/receptor signaling pathway now has been used as a new immune checkpoint for cancer immunotherapy. In this context, several HLA-G-targeted immunotherapies for advanced solid cancers have been launched; however, many challenges remain to be addressed. Conclusions: Cancer cell-restricted HLA-G expression is a promising therapeutic target for solid cancers. Antibody-specific blockade of the HLA-G molecule and/or HLA-G receptors, and HLA-G-targeted chimeric antigen receptor (CAR)-T cells or CAR-NK cells, alone or in combination with other checkpoints, may break down the immune tolerance of tumors.

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HLA-G: A Novel Immune Checkpoint for Solid Cancer Immunotherapy

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  • 发表日期：

    2025年

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  • Aifen Lin,
  • Wei-Hua Yan

摘要

Background: The distribution of human leukocyte antigen-G (HLA-G) is limited in physiological situations. Functionally, HLA-G is an important immunotolerant that comprehensively suppresses the biological functions of immune cells through HLA-G/receptor interactions. Abnormal induced expression of HLA-G has been detected in various types of cancer, and different degrees of HLA-G expressions are closely related to rapid tumor progression and/or worse clinical outcomes. Currently, HLA-G-based signaling is established as an immune checkpoint, and clinical trials of HLA-G-targeted immunotherapy for advanced solid cancers were launched in 2020. In this review, we focused on the important developments and achievements related to HLA-G as a novel immune checkpoint and the challenges that remain to be addressed for solid cancer immunotherapy. Methods: PubMed was comprehensively searched to identify relevant literature written in English and published on or before October 1, 2021. The keywords used for the search were HLA-G, cancer, malignancy, tumor, and prognosis combined with “and”/ “or.” Results: Cancer-restricted abnormally induced HLA-G expression is detected in most types of malignancies, while HLA-G expression is absent in non-tumorous adjacent tissues. By interacting with immune receptors such as immunoglobulin-like transcripts (ILT)-2, ILT-4, and killer cell immunoglobulin-like receptor (KIR)2DL4, HLA-G inhibits biological functions of different types of immune cells, favoring cancer cell immune evasion and disease progression. Induced HLA-G in cancer cells has been well acknowledged to be with enhanced tumor cell metastasis, advanced disease stage, and worse prognosis. The HLA-G/receptor signaling pathway now has been used as a new immune checkpoint for cancer immunotherapy. In this context, several HLA-G-targeted immunotherapies for advanced solid cancers have been launched; however, many challenges remain to be addressed. Conclusions: Cancer cell-restricted HLA-G expression is a promising therapeutic target for solid cancers. Antibody-specific blockade of the HLA-G molecule and/or HLA-G receptors, and HLA-G-targeted chimeric antigen receptor (CAR)-T cells or CAR-NK cells, alone or in combination with other checkpoints, may break down the immune tolerance of tumors.