ORIGINAL RESEARCH article
Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1612217
This article is part of the Research TopicCurrent Insights in Melanoma Immunology, Immune Escape and Immunotherapy AdvancesView all 12 articles
Programmed Cell Death-Driven Remodeling of the Melanoma Microenvironment Enables Prognostic Stratification and Therapeutic Prediction Running head: PCD and Immunotherapy in Melanoma
Provisionally accepted
- Peking University Third Hospital, Haidian, China
Select one of your emails
You have multiple emails registered with Frontiers:
Notify me on publication
Please enter your email address:
If you already have an account, please login
You don't have a Frontiers account ? You can register here
Background and Objective: Melanoma exhibits profound biological complexity, driven by immune evasion, phenotypic plasticity, and resistance to therapy. While programmed cell death (PCD) shapes tumor-immune interactions, its mechanistic landscape in melanoma remains incompletely defined. This study aims to comprehensively characterize PCD-related signatures and their associations with tumor heterogeneity, prognosis, and immunotherapeutic outcomes.Methods: Single-cell RNA sequencing data from melanoma cohorts (cutaneous and acral subtypes) were used to assess PCD activity via AUCellbased scoring across major cell types. Cell-type-specific analyses examined heterogeneity, metabolic dependencies, and pathway correlations. Intercellular communication was analyzed using CellChat. Bulk RNA sequencing data were then integrated to identify PCD-related gene signatures, and machine learning models (LASSO, Ridge, XGBoost) were applied to develop a prognostic model.Immune infiltration, immunogenomic correlations, and immunotherapy responses were further evaluated using ESTIMATE, CIBERSORT, TMB, IPS, and external ICB-treated cohorts.Results: Among all cell types, melanoma cells exhibited the highest PCD activation, with disulfidptosis, immunogenic cell death (ICD), and autosis being the most prominent. High PCD activity was linked to advanced clinical stage, lymphatic metastasis, and poor prognosis. Melanoma subpopulations with hyperactivated PCD displayed elevated copy number variation (CNV) burden, enhanced fibroblast/endothelial interactions, and invasive transcriptional profiles. A 15-gene prognostic signature was developed, effectively stratifying survival and immunotherapy response across multiple cohorts. Low-risk tumors demonstrated favorable immune infiltration (CD8⁺ T cells, M1 macrophages), higher tumor mutational burden (TMB), and greater immunogenicity, while high-risk tumors exhibited immune exclusion, cancerassociated fibroblast (CAF) enrichment, and adverse mutations.This study highlights the functional and clinical significance of PCD heterogeneity in melanoma and provides a validated prognostic model for patient stratification and therapeutic decision-making. These findings underscore the potential of targeting PCD dynamics as a novel approach in melanoma management.
Keywords: Melanoma, programmed cell death, Prognostic model, Immunotherapy, Tumor Microenvironment
Received: 15 Apr 2025; Accepted: 01 Aug 2025.
Copyright: © 2025 Hu, Li, Chai, Jin and Zhang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Long Zhang, Peking University Third Hospital, Haidian, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.