The elevated lactate and proton load in the tumor microenvironment (TME) may not only affect immune cells but also alter erythrocyte NADPH generation through the pentose phosphate pathway, enzymatic systems responsible for reducing methemoglobin back to hemoglobin (e.g., NADH-dependent cytochrome b5 reductase), and ion pumps such as Na+/K+-ATPase and Ca2+-ATPase (Figure 1) (22, 23) Such disruptions can result in diminished oxygen delivery, enhanced oxidative stress, and shortened erythrocyte lifespan. Here, HBG2 is linked to neoplasm.