One of the most troubling developments of 2021 has been the number of fertile-age women who have been led to believe that mRNA vaccines against severe acute respiratory syndrome coronavirus-2 [SARS-CoV-2, coronavirus disease 2019 (COVID-19)] can cause infertility via cross-reactivity of immune response. Specifically, cross-reactivity of developed antibodies to syncytin-1, a protein found in human cell fusion, placentation and recently identified in the envelope gene of a human endogenous defective retrovirus, HERV-W (see “Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis”. Nature. 2000;403:785–9. doi: 10.1038/35001608). The mechanism, evidence, and evaluation of the claim is presented concluding in a rejection due to lack of evidence.

A few pieces of research exist about the protective titer against severe acute respiratory syndrome (SARS) coronavirus 2 (CoV-2; SARS-CoV-2) in monkeys and humans in which the protection could be shown as dose-dependent. Early studies supposed that higher levels of pre-existing neutralizing antibodies (Nabs) against SARS-CoV-2 can potentially correlate with the protection to consequent infection. The data so far showed that cellular immunity is as essential as the humoral one. If needed, its presence can be beneficial if the titer of immunoglobulins is not optimal. It is also known that the immune response to the vaccine is similar to the one after natural infection with a production of very high naturalization titers antibodies. However, medical community is still unaware of the immunoglobulin titer needed for protection against the virus. The answers to the questions regarding correlates of protection are yet to be discovered. Still, no studies indicate a specific virus-Nab titer, so one can assume a patient is protected from being infected in the future. The evoked immunological response is indeed encouraging, but a future investigation is needed. Nonetheless, it remains a mystery how long the immunity lasts and whether it will be enough to shield the patients in the long run. Therefore, identifying immune protection correlations, including neutralization titer of antibodies and T cell immune response against SARS-CoV-2, could give a clue. Unfortunately, recent studies in the field have been more controversial than concise, and the data available is far from consensus.

Endometriosis is an inflammatory oestrogen-dependent chronic disease and is mainly expressed by pain and increased infertility. Several studies showed an increased prevalence of autoimmune systemic diseases and various autoantibodies in endometriosis. The association of these autoimmune markers and diseases could raise the fact that endometriosis is an authentic autoimmune or inflammatory disease and thus could argue for the use of immunomodulatory therapies. Usually, it is considered that the autoantibodies did not directly act in endometrium implants growth, and could be rather implicated in endometriosis-related infertility. The use of immunomodulatory strategies could be an important alternative or additional strategy to the use of hormones and surgery but need prospective well-designed trials.

In recent decades, abundant methods for targeted tumor cell immunotherapy have been developed. It was recently discovered that excellent curative effects observed in hematological tumors cannot be achieved in solid tumors, as serious side effects will occur. These are all derived from engineered adaptive immune cells, the use of which will bring limitations. γδT cells have a unique ability to respond to a variety of tumor cells while linking innate immunity and adaptive immunity, and thus, they are an ideal source of therapeutic allogeneic cells. This review introduces strategies that can optimize the clinical application of γδT cells to provide novel ideas for adoptive immunotherapy in the future.

γδ T cells are one of the immune cell types that express antigen receptors. γδ T cells are able to recognize pathogens or cancer cells independently of human leukocyte antigen restriction, which is an important feature of αβ T cells. Therefore, γδ T cells are considered the bridge between innate and adaptive immunity. These cells exhibit important roles in immune surveillance, exert immune defense against tumors and have become promising effector cells for cancer immunotherapy. However, in particular circumstances, the tumor microenvironment seems to render γδ T cells immunosuppressive and even tumor-promoting, emphasizing the importance of regulating γδ T functions in realizing their translation into practical cancer immunotherapy. In recent years, increasing evidence has demonstrated that the intratumoral and peritumoral microbiota can have complex effects on tumor immunology. Thus, understanding the role of microbiota in the crosstalk between γδ T cells and tumors will provide insights for developing adjuvant immunotherapy with precise regulation of tumor-related microbiota. In the present review, the effects of microbiota on γδ T cell receptor repertoire and the roles of microbiota in some common tumors will be discussed, with implications for future cancer therapy.

In recent years, immunologists have been working to utilize the functional mechanism of the immune system to research new tumor treatment methods and achieved a major breakthrough in 2013, which was listed as one of the top 10 scientific breakthroughs of 2013 by Science magazine (see “Cancer immunotherapy”. Science. 2013;342:1417. doi: 10.1126/science.1249481). Currently, two main methods are used in clinical tumor immunotherapy: immune checkpoint inhibitors and chimeric antigen receptor (CAR) T cells. Clinical responses to checkpoint inhibitors rely on blockade of the target neoantigens expressed on the surfaces of tumor cells, which can inhibit T cell activity and prevent the T cell immune response; therefore, the therapeutic effect is limited by the tumor antigen expression level. While CAR-T cell therapy can partly enhance neoantigen recognition of T cells, problems remain in the current treatment for solid tumors, such as restricted transport of adoptively transferred cells to the tumor site and off-targets. Immunologists have therefore turned their attention to γδ T cells, which are not restricted by the major histocompatibility complex (MHC) for neoantigen recognition and are able to initiate a rapid immune response at an early stage. However, due to the lack of an understanding of the antigens that γδ T cells recognize, the role of γδ T cells in tumorigenesis and tumor development is not clearly understood. In the past few years, extensive data identifying antigen ligands recognized by γδ T cells have been obtained, mainly focusing on bisphosphonates and small-molecule polypeptides, but few studies have focused on protein ligands recognized by γδ T cells. In this paper, it is reviewed and analyzed that the tumor-associated protein ligands of γδ T cells that have been discovered thus far, hoping to provide new ideas for the comprehensive application of γδ T cells in tumor immunotherapy.

Antitumor immunity relies on the ability of T cells to recognize and kill tumor targets. γδ T cells are a specialized subset of T cells that predominantly localizes to non-lymphoid tissue such as the skin, gut, and lung where they are actively involved in tumor immunosurveillance. γδ T cells respond to self-stress ligands that are increased on many tumor cells, and these interactions provide costimulatory signals that promote their activation and cytotoxicity. This review will cover costimulatory molecules that are known to be critical for the function of γδ T cells with a specific focus on mouse dendritic epidermal T cells (DETC). DETC are a prototypic tissue-resident γδ T cell population with known roles in antitumor immunity and are therefore useful for identifying mechanisms that may control activation of other γδ T cell subsets within non-lymphoid tissues. This review concludes with a brief discussion on how γδ T cell costimulatory molecules can be targeted for improved cancer immunotherapy.

γδ T cells express unique T cell receptor (TCR) γ and TCR δ chains, with structural and functional heterogeneity. Taking advantage of the diverse γδ TCR repertoire or other ligand-receptor interactions, γδ T cells can recognize a broad spectrum of tumor-associated antigens (TAAs) in a major histocompatibility complex (MHC)-independent manner, thereby activating downstream pleiotropic effects. γδ T cells recruited into the tumor microenvironment can act as effector cells to mediate cancer immune surveillance. Their advantage lies in the ability to perceive tumors with a low mutation load, thus establishing the first line of defense against pathogens. Activated γδ T cells exhibit strong cytotoxic activity and cytokine secretion functions and are effective antitumor lymphocytes with simple and direct recognition modes and rapid responses. However, the clinical application of tumor-infiltrating γδ T cells has certain limitations. First, γδ T cells exposed to complicated cytokine networks are potentially affected by multiple inhibitory mechanisms. Additionally, these cells show highly flexible and dynamic plasticity and are extremely easily polarized into regulatory phenotypes. This review further emphasizes the diversified cross-talk between γδ T cells and other immune cells. Effective immunity of the body is often manifested by counterbalance under mutual restriction. Therefore, an in-depth understanding of γδ T cells that play conflicting roles in the tumor microenvironment is necessary. These cells may be a key factor ultimately mediating the deviation of the antagonistic response between tumor inhibition and tumor promotion. Finally, it retrospectively analyze the activation strategies and clinical relevance of existing γδ T cell adoptive immunotherapies. According to current challenges, there is a need to explore innovative immunotherapies, maximize the tumor-killing efficacy of γδ T cells, and attenuate or eliminate tumor immunosuppression. It is hoped that the host immune status can be accurately predicted and gradually advance γδ T cell precise individualized medicine.