Tumor antigens provide the molecular interface between malignant transformation and host immunity, but their biological significance is determined by more than their molecular existence. Antigen clonality, abundance, processing, human leukocyte antigen (HLA) presentation, dendritic-cell function, T-cell recognition, spatial immune organization, and the surrounding tumor microenvironment (TME) collectively determine whether an antigen becomes immunologically visible and therapeutically actionable. Across cancer progression, tumor-cell antigenic states and the TME undergo reciprocal selection: immune pressure can eliminate highly visible clones while favoring antigen-loss variants, HLA defects, immune exclusion, suppressive myeloid and stromal states, and treatment-resistant populations. Recent single-cell, spatial and three-dimensional imaging, as well as immunopeptidomic studies show that this evolution is heterogeneous across tumor regions and anatomical compartments rather than a uniform linear process. This review therefore advances an antigen-TME co-evolution framework linking primary tumors, lymphatic and nodal immune compartments, systemic dissemination, distant metastatic niches, therapy, minimal residual disease, and recurrence. It critically evaluates the strengths and limitations of the classical immunoediting model; compares melanoma, breast, colorectal, lung, prostate, sarcoma, and virus-associated cancers according to antigen source, clonality, presentation competence, immune architecture, and dominant therapeutic bottleneck; and examines clinical translation through checkpoint blockade, cellular therapy, vaccines, antibodies, antibody-drug conjugates, immunopeptidomics, and computational antigen prediction. Particular attention is given to the gap between predicted peptide binding and verified presentation or immunogenicity, the need for longitudinal rather than single-biopsy profiling, and the requirement for prospective validation of artificial-intelligence models. The central conclusion is that tumor antigens become clinically meaningful only when antigenic state and microenvironmental context are assessed together, providing a more rigorous foundation for precision cancer immunotherapy.
The maintenance of esophageal motility relies on the coordinated actions of the mucosa, nervous system, and muscular layers. The mucosal layer not only serves as a physical barrier but also functions as a sensory interface that detects intraluminal stimuli and contributes to local regulation through the release of bioactive molecules. As the central regulatory component, the nervous system comprises an integrated network formed by the intrinsic enteric nervous system and the extrinsic sympathetic and parasympathetic nervous systems, which collectively integrate afferent signals and coordinate muscular activity. Immune mechanisms also play an important modulatory role in the regulation of esophageal motility. Immune cells, including mast cells, eosinophils, T cells, and macrophages, engage in bidirectional interactions with neuropeptides and the esophageal microbiota, thereby contributing to motility regulation through immune–neural interactions. The muscular layer, composed of striated and smooth muscle, serves as the effector component of motility, with the rhythm and intensity of contraction determining the efficiency of esophageal propulsion and clearance. Accordingly, with esophageal motility as its central focus, this review examines the interactions and coordination among the esophageal mucosa, nervous system, and musculature. Based on a systematic review of recent studies investigating the microscopic regulation of neural and muscular function by neurotransmitters, immune cells, sensory nerve endings, and metabolites derived from the esophageal microbiota, this review elucidates the critical role of the nervous system, particularly the enteric nervous system, in linking mucosal signals to muscular responses, together with its associated immunoregulatory mechanisms. It further explores how these components act synergistically to maintain normal esophageal motility and provides a theoretical basis for pathophysiological research into esophageal motility disorders.
Recurrent implantation failure (RIF) describes a clinical outcome rather than a single diagnosis or immune disorder. During progesterone-driven decidualization, changes in stromal metabolism and epithelial secretion accompany the production of signals that support uterine natural killer (uNK) cell residency. Autophagy contributes to these changes, although its role in RIF is unresolved. Genetic studies in mice and human stromal cells implicate autophagy-related proteins in progesterone responses and decidual differentiation. Some RIF tissue studies, however, report increased autophagy-associated signals. Increased flux accompanies impaired progesterone responses in some stromal models and improved decidualization in others. These contrasting findings may reflect the need to maintain autophagic activity within a suitable range for each cell compartment and cycle phase, rather than a uniform deficit. Progesterone-responsive stromal cells release interleukin 15 (IL-15) and related signals that recruit and program uNK cells. Their residency may also depend on epithelial secretion, adhesion, and matrix remodeling. In cycling human endometrium, activated uNK cells contribute to tissue quality control by clearing senescent maternal decidual cells; the embryo is not the target of this process. Single-cell and spatial studies of RIF endometrium have identified altered epithelial, stromal, and NK states. Whether progesterone resistance causes these cellular changes and, in turn, implantation failure remains unknown. This review examines the evidence for these relationships and the experiments needed to assess autophagic flux beyond static markers and uNK function beyond cell abundance. Current evidence does not support routine NK testing or autophagy-directed treatment in RIF.
Elise Sintim-Aboagye, Huy Quang Quach, Indrani Mukherjee, Will Sherman, Katelyn T. Nguyen, Neil Ferland, Sheila Farnan, Kamila Otrubova, Namisha Verma, Dawn Littlefield, Sohan Punia, Erica Johnson, Mark Blackstad, Mark R. Schleiss, Andrew P. Norgan, Clive M. Gray, Elizabeth Ann L. Enninga, Rana Chakraborty
Human cytomegalovirus (CMV) is the leading infectious cause of congenital birth defects worldwide. The placenta is a major route of vertical transmission, and both immune and trophoblast cells are susceptible to CMV infection. This study aimed to spatially characterize gene and protein expression changes associated with CMV infection in the human placenta. In this exploratory study, CMV+ and control placentae were analyzed using the NanoString GeoMx Digital Spatial Profiler to assess compartment-specific transcriptomic and proteomic profiles in trophoblast and immune cell populations. CMV+ placentae showed increased immune activation in both trophoblast and immune cells, including pathways related to immune-cell proliferation, differentiation, lymphopoiesis, and T-cell development. Infected placentae also showed altered tissue repair and remodeling pathways, along with changes in proapoptotic proteins and cell death-associated transcripts. Given the limited sample size, these findings are descriptive and hypothesis-generating. They provide preliminary insight into CMV-associated placental immune dysregulation and identify candidate pathways for investigation in larger, prospective studies.
