Cancer cells can develop secondary resistance to ICIs through immune exhaustion, which includes the upregulation of different immune checkpoints on cytotoxic T cells with chronic antigen exposure including lymphocyte activation gene-3 (LAG-3), T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), and T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3), secretion of immunosuppressive cytokines, tumor neoantigen downregulation, and a defective formation of memory T cells. This evidence concerns the gene LAG3 and neoplasm.