This review provides an in-depth analysis of the biology of B and T lymphocyte attenuator (BTLA), a crucial immune checkpoint receptor, and its role in cancer. BTLA, which interacts with herpes virus entry mediator (HVEM), plays a key role in regulating immune responses by inhibiting T-cell activation and proliferation. Abnormal BTLA expression is observed in various cancers, often associated with impaired anti-tumor immunity and unfavorable outcomes. Preclinical studies have shown that BTLA-targeted therapies can improve treatment outcomes and enhance antitumor immunity. The review covers the structure and signaling mechanisms of BTLA, its expression patterns in different immune cells, and its role in cancer immunosurveillance. It also explores the potential of BTLA as a prognostic factor and discusses recent advancements in BTLA blockade as a therapeutic strategy in cancer immunotherapy. The review highlights the complex regulatory mechanisms involving miRNAs in modulating BTLA expression and its implications for cancer. Additionally, it examines the expression and clinical significance of BTLA in various types of cancers, including hematological, lung, melanoma, gastrointestinal, hepatocellular, oral, thyroid, gynecologic, and neurological cancers. The findings suggest that BTLA may serve as a predictive biomarker and a therapeutic target in cancer treatment.This review provides an in-depth analysis of the biology of B and T lymphocyte attenuator (BTLA), a crucial immune checkpoint receptor, and its role in cancer. BTLA, which interacts with herpes virus entry mediator (HVEM), plays a key role in regulating immune responses by inhibiting T-cell activation and proliferation. Abnormal BTLA expression is observed in various cancers, often associated with impaired anti-tumor immunity and unfavorable outcomes. Preclinical studies have shown that BTLA-targeted therapies can improve treatment outcomes and enhance antitumor immunity. The review covers the structure and signaling mechanisms of BTLA, its expression patterns in different immune cells, and its role in cancer immunosurveillance. It also explores the potential of BTLA as a prognostic factor and discusses recent advancements in BTLA blockade as a therapeutic strategy in cancer immunotherapy. The review highlights the complex regulatory mechanisms involving miRNAs in modulating BTLA expression and its implications for cancer. Additionally, it examines the expression and clinical significance of BTLA in various types of cancers, including hematological, lung, melanoma, gastrointestinal, hepatocellular, oral, thyroid, gynecologic, and neurological cancers. The findings suggest that BTLA may serve as a predictive biomarker and a therapeutic target in cancer treatment.