PGE2 can promote tumor initiation, progression, angiogenesis, transformation, metastasis, and recurrence in EC, GC, HCC, and CRC by activating numerous intracellular signaling pathways, as described in detail herein. In addition to blunting responsiveness to neoadjuvant chemoradiotherapy and NSAID/COXIB treatments, PGE2 upregulation substantially worsens the overall prognosis. It also enhances epigenetic dysfunction due to DNA methylation of various tumor suppressor genes, as shown in Figure 2.