From the data presented, it is evident that hypoxia-/HIF-1α-driven features of the TME, such as ADO and lactate accumulation, extracellular acidosis, VEGF overexpression, and VEGF-R activation, and PS-externalization from the inner to the outer leaflet of tumor cells or tumor-derived exosomes are accomplices (“fatal sextet” of TME) sabotaging spontaneous and therapeutically induced antitumor immune responses. This evidence concerns the gene HIF1A and neoplasm.