The Double Engines and Single Checkpoint Theory of Endometriosis

Endometriosis is a chronic disease characterized by the ectopic localization of the endometrial tissue in the peritoneal cavity. Consequently, it causes local pathological changes and systemic symptoms, affecting at least one in every ten women. This disease is difficult to diagnose early, it is prone to dissemination, is difficult to eradicate, tends to recur, and is regarded as "a cancer of no kill". Indeed, the development of endometriosis closely resembles that of cancer in the way of mutagenesis, pelvic spreading, and immunological adaptation. While retrograde menstruation has been regarded as the primary cause of endometriosis, the role of ovulation and menstrual stimuli in the development of endometriosis has long been overlooked. The development of ovarian and peritoneal endometrioses, similar to the development of high-grade serous carcinoma in the fallopian tube fimbriae with intraperitoneal metastasis, depends highly on the carcinogens released during ovulation. Moreover, endometriosis carries an extremely hypermutated genome, which is non-inferior to the ultra-mutated endometrial cancer. The hypermutation would lead to an overproduction of new proteins or neoantigens. Because of this, the developing endometriosis may have to turn on the PD-1/PDL-1 "self-tolerance" checkpoint to evade immune surveillance, leaving an Achilles tendon for an immune checkpoint blockade. In this review, we present the double engines and single checkpoint theory of the genesis of endometriosis, provide the current pieces of evidence supporting the hypothesis, and discuss the new directions of prevention and treatment.