Malignancy has traditionally been viewed as a genetic disease driven by mutation and clonal selection. However, growing evidence indicates that tumors also exploit conserved developmental and immunological programs that predate cancer development. Among these, placentation stands out as a prominent biological analogy. During pregnancy, trophoblast cells exhibit rapid growth, controlled invasion, angiogenesis, metabolic adaptability, and localized immune tolerance, features that closely resemble those of aggressive tumors. This review revisits the trophoblastic theory of cancer and suggests that a specific biologically defined subset of solid tumors may evolve through a placentation-like system rather than directly from a trophoblastic lineage. We examine evidence showing that progesterone, acting via nuclear progesterone receptors and membrane-associated mediators such as PGRMC1, can induce immune-regulatory effectors, including progesterone-induced blocking factors (PIBF) and HLA-G, in preclinical models. We also discuss important caveats: HLA-G and metabolic reprogramming are not unique to placentation but can also be triggered by hypoxia, inflammatory cytokines, and epigenetic plasticity. Therefore, we do not argue for a trophoblastic origin but for the convergent activation of conserved survival strategies, which, when sustained and protected from immune attack, create a tumor-permissive environment. Finally, we propose a biomarker-driven, ethically guided clinical framework to evaluate the use of progesterone receptor antagonists or modulators in cancer treatment. The trophoblastic model, as a systems-level hypothesis, provides testable predictions that combine endocrine biology with modern immuno-oncology and may uncover previously unrecognized therapeutic vulnerabilities in cancers. • Cancer may reflect pathological reactivation of placental immune tolerance programs. • Progesterone signaling supports immune evasion and metabolic adaptation in defined tumor subsets. • HLA-G and PIBF mediate placental-like suppression of antitumor immune responses. • Progesterone receptor antagonists may reverse endocrine-driven immune exclusion and resistance.
Hoang et al. (Thu,) studied this question.