Immune checkpoint inhibitors for the treatment of solid tumors and lymphoma in the past 26 years (2000–2025)

Cancer immunotherapy originated from the use of Coley's toxins at the end of the nineteenth century. However, immunotherapy had not made great strides in cancer treatment until the discovery of immune checkpoints among which cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1) are the most representative ones. Since the first CTLA-4 inhibitor ipilimumab started the first clinical trial in 2000, immune checkpoint inhibitor (ICI) therapy has gradually emerged as the most successful and widely applied strategy in the field of cancer immunotherapy, revolutionizing treatment paradigms across a broad spectrum of malignancies. Recently, the approvals of monoclonal antibodies targeting lymphocyte activation gene-3 (LAG-3) and novel bispecific antibodies targeting immune checkpoints may indicate the next wave of ICI agents development in cancer immunotherapy. In this review, we aimed to provide a comprehensive overview and in-depth discussion covering the current ICI treatment landscape in the past 26 years (2000-2025), indications and limitations of efficacy-predicting biomarkers, immune-related adverse events, resistance mechanisms and overcoming strategies, as well as future directions of ICI therapy.