Survival by Design: Cell Fate Dynamics in Classical Hodgkin Lymphoma.

Authors

Matei Seleusan, Diana Cenariu, Diana Gulei, David Kegyes, Adrian Bogdan Tigu, Sadia Riaz, Mihnea Zdrenghea, Ciprian Tomuleasa

Published in

Critical reviews in oncology/hematology. Pages 105651. Oct 15, 2026. Epub Oct 15, 2026.

Abstract

Classical Hodgkin lymphoma (cHL) is singular because rare Hodgkin and Reed-Sternberg (HRS) cells survive within an abundant inflammatory tumor microenvironment (TME) - despite originating from germinal center (GC) B cells that would normally be negatively selected, they persist through coordinated disruption of lineage fidelity, immune recognition, and cell-death execution. The present review integrates mechanistic, translational, and therapeutic evidence on apoptosis resistance, survival signaling, microenvironmental support, immune evasion, Epstein-Barr virus-associated rescue mechanisms, and senescence-like phenotypes in cHL, with particular emphasis on how these processes converge to stabilize an aberrant HRS-cell fate by raising the apoptotic threshold. HRS cells retain several elements of apoptotic competence, including death receptors, functional mitochondrial apoptotic machinery, and frequently wild-type TP53; however, these factors are functionally restrained by multiple antagonistic mechanisms: c-FLIP inhibits pro-caspase-8 activation, constitutive NF-κB, JAK/STAT and PI3K/AKT signaling sustain survival, BCL-2-superfamily overexpression confers resistance to intrinsic apoptotic stimuli, MDM2 overactivity suppresses p53, and microenvironment-derived secretory products and contact-dependent ligands provide stabilizing support. The inflammatory niche reinforces HRS-cell persistence by converting immune proximity into immune privilege through altered antigen presentation, PD-1/PD-L1 signaling, spatially inhibitory rosetting structures, regulatory T-cell prevalence, M2-macrophage polarization, and cytokine-mediated paracrine and autocrine survival circuits. Emerging evidence indicates that Reed-Sternberg cells (RS) acquire senescence-like features and secretory programs that contribute to constructing the inflammatory niche. cHL can therefore be understood as a malignancy of failed fate execution, in which apoptosis, differentiation and immune clearance remain available but are rendered non-executable by convergent intrinsic and microenvironmental survival circuits.

PMID:
42880615
Bibliographic data and abstract were imported from PubMed on 16 Oct 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.