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Advances in Single-Cell and Spatial Transcriptomics: Decoding Tumor Heterogeneity and...
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Advances in Single-Cell and Spatial Transcriptomics: Decoding Tumor Heterogeneity and Microenvironment

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: 31 October 2026 | Viewed by 4074

Editor

Dr. Guanhu Yang

E-Mail Website
Guest Editor
Traditional Chinese Medicine, Macau University of Science and Technology, Taipa, Macao
Interests: multi-omics; tumor immunity; integrative medicine; multimodal models

Special Issue Information

Dear Colleagues,

Tumor heterogeneity and microenvironment (TME) interactions drive cancer progression and therapy resistance. Single-cell sequencing (scRNA-seq, scATAC-seq) and spatial transcriptomics resolve the cellular diversity and spatial architecture of tumors at an unprecedented quality. This Research Topic seeks studies leveraging these technologies to decode the molecular mechanisms of oncogenesis, immune evasion, and treatment failure, translating insights into precision oncology.

We welcome original research and reviews on the following areas:

  • Tumor evolution—clonal dynamics via single-cell multi-omics.
  • Spatial TME—immune/stromal interactions, metabolic niches.
  • Resistance mechanisms—rare cell states and spatial niches in chemo/immunotherapy resistance.
  • Translational innovations—spatial biomarkers, computational tools, and therapeutic targeting.

Dr. Guanhu Yang
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • single-cell sequencing
  • spatial transcriptomics
  • tumor microenvironment
  • heterogeneity
  • immunotherapy resistance

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Published Papers (2 papers)

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Research

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25 pages, 12112 KB  
Article
A Pan-Cancer Multi-Omics Analysis of CAD: Integrating CRISPR and Metabolomics Data to Unravel the Metabolic–Immune Axis and Immunotherapy Response
by Yiyan Li, Aoxue Xing, Wenzheng Li, Yiman Zhang, Kejuan Zhang, Tianhao Xie, Gang Wu and Wei Zhang
Biomedicines 2026, 14(6), 1218; https://doi.org/10.3390/biomedicines14061218 - 28 May 2026
Viewed by 337
Abstract
Background: CAD (Carbamoyl-Phosphate Synthetase 2, Aspartate Transcarbamylase, and Dihydroorotase) is a pivotal tri-functional enzyme complex associated with the rate-limiting steps of the de novo pyrimidine biosynthetic pathway. Despite its established metabolic role, the multi-dimensional involvement of CAD in the pan-cancer landscape—specifically regarding its [...] Read more.
Background: CAD (Carbamoyl-Phosphate Synthetase 2, Aspartate Transcarbamylase, and Dihydroorotase) is a pivotal tri-functional enzyme complex associated with the rate-limiting steps of the de novo pyrimidine biosynthetic pathway. Despite its established metabolic role, the multi-dimensional involvement of CAD in the pan-cancer landscape—specifically regarding its regulation of the metabolic–immune axis and its impact on immunotherapy response—remains to be fully elucidated. Methods: We performed a systematic pan-cancer multi-omics analysis integrating TCGA, GTEx, and DepMap datasets to evaluate CAD expression, genomic alterations, and diagnostic potential. In addition, multiple immunotherapy cohorts were integrated for meta-analysis, and metabolomic data were incorporated to explore CAD-associated metabolic features. Results: CAD was significantly upregulated in 17 cancer types, with protein-level evidence supporting this trend. CAD also showed high diagnostic accuracy in several malignancies, particularly LAML and CHOL (AUC approximately 1.0). In immunotherapy-related analyses, CAD expression was positively associated with TMB, MSI, and initial therapeutic response, but was also linked to worse long-term overall survival in pooled cohorts (HR = 1.42, 95% CI: 1.19–1.70). Integrative metabolomic analyses further suggested that high CAD expression was associated with pyrimidine metabolite accumulation and altered amino acid metabolism, indicating a potential link between CAD-related metabolic reprogramming and the tumor immune microenvironment. Conclusions: CAD may represent a promising candidate biomarker across multiple malignancies. Notably, its association with immunotherapy-related features, together with the observed discordance between response-associated signals and long-term survival, warrants further mechanistic and clinical validation. Full article
(This article belongs to the Special Issue Advances in Single-Cell and Spatial Transcriptomics: Decoding Tumor Heterogeneity and Microenvironment)
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Review

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21 pages, 1228 KB  
Review
Single-Cell Sequencing Unravels Pancreatic Cancer: Novel Technologies Reveal Novel Aspects of Cellular Heterogeneity and Inform Therapeutic Strategies
by Keran Chen, Zeyu Chen, Jinai Wang, Mo Zhou, Yun Liu, Bin Xu, Zhi Yu, Yiming Li, Guanhu Yang and Tiancheng Xu
Biomedicines 2025, 13(12), 3024; https://doi.org/10.3390/biomedicines13123024 - 10 Dec 2025
Cited by 7 | Viewed by 3188
Abstract
Single-cell sequencing (scRNA-seq) has emerged as a pivotal technology for deciphering the complex cellular heterogeneity and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC), positioning it as a critical tool for informing novel therapeutic strategies. This review explores how scRNA-seq reveals diverse cellular [...] Read more.
Single-cell sequencing (scRNA-seq) has emerged as a pivotal technology for deciphering the complex cellular heterogeneity and tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC), positioning it as a critical tool for informing novel therapeutic strategies. This review explores how scRNA-seq reveals diverse cellular subpopulations and their functional roles within the PDAC TME, including malignant epithelial cells with transitional phenotypes, heterogeneous cancer-associated fibroblasts (CAFs), functionally distinct immune cells such as tumor-associated neutrophils (TANs) and macrophages (TAMs), and actively participating neural components like Schwann cells. These cellular constituents form specialized functional units that drive tumor progression, immune evasion, neural invasion, and therapy resistance through metabolic reprogramming, immunosuppressive signaling, and cellular plasticity. The review further examines technological advances in single-cell sequencing from 2023 to 2025, focusing on sample preprocessing innovations, multi-omics integration (combining transcriptomics with epigenomics and proteomics), spatial resolution enhancements, and customized computational tools that address PDAC-specific challenges. Clinically, single-cell sequencing enables precise cellular subtyping, identification of novel biomarkers, and development of personalized therapeutic approaches, including combination therapies targeting specific cellular subpopulations and their interactions. Despite these advances, significant challenges remain in standardizing clinical applications such as liquid biopsy for early detection and tumor microenvironment assessment for diagnostic staging, validating biomarkers like CLIC4, GAS2L1, Cytokeratins, Vimentin and N-cadherin in circulating tumor cells, and comprehensively integrating multi-omics data. Future research focusing on both technology refinement and biological validation will be essential for translating single-cell insights into improved diagnostic and therapeutic outcomes for pancreatic cancer. Full article
(This article belongs to the Special Issue Advances in Single-Cell and Spatial Transcriptomics: Decoding Tumor Heterogeneity and Microenvironment)
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