BTLA is an inhibitory immune checkpoint that regulates immune responses by interacting with its ligand, HVEM. It plays a critical role in maintaining immune homeostasis by inhibiting T and B-cell activation and proinflammatory cytokine production. In cancer, BTLA is often overexpressed, leading to impaired anti-tumor immunity and poor patient outcomes. Preclinical studies have shown that BTLA-targeted therapies can improve treatment outcomes and enhance antitumor immunity. This review summarizes the biology of BTLA, its role in various cancers, and its potential as a prognostic factor. It also explores the latest research on BTLA blockade in cancer immunotherapy, offering hope for more effective cancer treatments. BTLA is expressed on various immune cells, including T-cells, B-cells, and dendritic cells. Its expression is regulated by various factors, including gene expression, epigenetic modifications, and miRNA regulation. In cancer, BTLA expression is associated with poor prognosis and resistance to immunotherapy. However, BTLA blockade has shown promise in enhancing immune responses and improving patient outcomes in various cancers, including melanoma, lung cancer, gastrointestinal cancers, hepatocellular carcinoma, and thyroid cancer. The role of BTLA in cancer immunotherapy is an active area of research, with ongoing studies exploring its potential as a therapeutic target.BTLA is an inhibitory immune checkpoint that regulates immune responses by interacting with its ligand, HVEM. It plays a critical role in maintaining immune homeostasis by inhibiting T and B-cell activation and proinflammatory cytokine production. In cancer, BTLA is often overexpressed, leading to impaired anti-tumor immunity and poor patient outcomes. Preclinical studies have shown that BTLA-targeted therapies can improve treatment outcomes and enhance antitumor immunity. This review summarizes the biology of BTLA, its role in various cancers, and its potential as a prognostic factor. It also explores the latest research on BTLA blockade in cancer immunotherapy, offering hope for more effective cancer treatments. BTLA is expressed on various immune cells, including T-cells, B-cells, and dendritic cells. Its expression is regulated by various factors, including gene expression, epigenetic modifications, and miRNA regulation. In cancer, BTLA expression is associated with poor prognosis and resistance to immunotherapy. However, BTLA blockade has shown promise in enhancing immune responses and improving patient outcomes in various cancers, including melanoma, lung cancer, gastrointestinal cancers, hepatocellular carcinoma, and thyroid cancer. The role of BTLA in cancer immunotherapy is an active area of research, with ongoing studies exploring its potential as a therapeutic target.