Enhancing tumor mutational burden (i.e., releasing intracellular bodies like mRNA, ATP, HMGB1, Calreticulin, and Heat shock proteins in the lymph node microenvironment) triggers the immune system in two different ways of activating antigen-presenting cells (APCs) and raising the tumor antigen concentration in the lymphatic vessels as a systemic circulating route. This evidence concerns the gene HMGB1 and neoplasm.