Collection

Dissecting and Targeting the Heterogeneity and Plasticity of the Tumor Ecosystem

Editors

Dean G. Tang

Distinguished Professor and Chair, Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center (RPCCC), USA

Research Interests: Cancer cell heterogeneity and plasticity; cancer stem cells; prostate cancer; non-coding RNAs and epigenetic regulation of cell state
E-Mail | Website
Justin D. Lathia

Professor, Department of Cancer Sciences, Cleveland Clinic Research, Cleveland, OH, USA
Rose Ella Burkhardt Brain Tumor Center, Cleveland Clinic, Cleveland, OH, USA
Case Comprehensive Cancer Center, Cleveland, OH, USA
Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, Cleveland, OH, USA
Department of Clinical Medicine and Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Copenhagen, Denmark

Research Interests:
Malignant brain tumors; glioblastoma; cancer stem cells; cell-cell communication; cell adhesion; sex differences

E-Mail | Website

Introduction

Primary tumors are abnormally developed and dysregulated organs that comprise a unique ecosystem. Disseminated and metastatic cancers represent a systemic disease that often reflects the macro- and microenvironments of the ‘soil’ organs. In both settings, in addition to malignant cells, there are myriad of non-cancer cells that are inter-mingled with and frequently overshadow the tumor parenchyma. These include stromal cells (different subtypes of fibroblasts, smooth muscle cells, myofibroblasts), immune and inflammatory cells (both innate and adaptive), vasculature cells (blood vessel endothelial cells, pericytes, lymphatic and glymphatic endothelial cells), neuronal and neural cells and nerves. These non-malignant cells constitute the so-called tumor micro-environment or TME, and they constantly cross-talk to cancer cells during progression and therapies and play intricate roles in developing treatment resistance and mediating cancer relapse. Strikingly, the tumor ecosystem also exhibits sex- and aging-associated differences and dynamics. Technical advances in the past decade, especially single-cell multi-Omics (e.g., scRNA-seq, scATAC-seq, snRNA-/ATAC-seq), spatial Omics (spatial transcriptomics and spatial proteomics), and multi-spectral imaging platforms (e.g., IMC, Vectra, Phenocycler), have generated unprecedented details about the cellular (and extracellular) compositions of the tumor ecosystem, and have identified numerous novel therapeutic targets. In this Special Issue with a broad theme “Dissecting and Targeting the Heterogeneity and Plasticity of the Tumor Ecosystem”, we have collected manuscripts (Reviews, Perspectives, Research Articles) that:

Report the heterogeneity and plasticity of cancer cell subpopulations as well as non-cancer cell types including stromal, neural and immune/inflammatory cells
Elucidate evolutionary dynamics of and interactions/relationships between cancer cell and stromal/immune cell subpopulations
Dissect molecular, transcriptomic, epigenetic/epigenomic, and cellular mechanisms driving the cellular plasticity and cell state transitions in both cancer and non-cancer cell compartments
Report and dissect the heterogeneity of extracellular and systemic factors in cancer patients including (but not limited to) CTCs, cfDNAs, ctDNAs, and EVs
Demonstrate how the cellular heterogeneity and plasticity impact and promote cancer progression, therapeutic resistance, and metastasis
Expound on sex and aging as important biological variables associated with and driving the evolution of cancer ecosystem
Develop and summarize novel therapeutic strategies, particularly immunotherapeutic approaches (e.g., BsAb, ADC, BiTE, CAR-T), that aim to target the cancer ecosystem including the tumor immune microenvironment.

We hope that you will be as excited as we are reading through these timely papers!

Manuscript Submission Information

Submitted manuscripts should not have been published previously, nor been under consideration for publication elsewhere (except conference proceedings). All manuscripts will be thoroughly refereed through a single-blinded peer-review process. A guide for manuscript submission is available at Submission Instructions.

Published Papers

Review
Metabolic plasticity and radiotherapy response in prostate cancer: Emerging roles for extracellular vesicles

Ken You, Rashmi Gupta, Joseph Bucci, Qi Wang, Jie Ni

Cancer Heterogeneity and Plasticity https://doi.org/10.47248/chp2603030010

Received: Apr 22, 2026 | Accepted: Jul 11, 2026 | Published: Jul 17, 2026

Perspective
When immune landscapes diverge: How immune cell heterogeneity shapes cancer immunotherapy response

Jessie L. Chiello, Nijamuddin Shaikh, AJ Robert McGray

Cancer Heterogeneity and Plasticity https://doi.org/10.47248/chp2603030009

Received: Mar 31, 2026 | Accepted: Jun 23, 2026 | Published: Jul 10, 2026

Review
Hippo-YAP/TAZ signaling in gastric cancer: orchestrating epithelial-stromal heterogeneity, plasticity, and therapy resistance

Junsong Zhao, Curt Balch, Dipti Athavale, Yanting Zhang, Xiaodan Yao, Mikel Ghelfi, Madeline B Torres, Young Ki Hong, Jamin Morrison, Francis Spitz, Generosa Grana, Shumei Song

Cancer Heterogeneity and Plasticity https://doi.org/10.47248/chp2603030008

Received: Mar 25, 2026 | Accepted: Jun 15, 2026 | Published: Jul 2, 2026

Editorial
Dissecting and Targeting the Heterogeneity and Plasticity of the Tumor Ecosystem

Dean G. Tang, Justin D. Lathia

Cancer Heterogeneity and Plasticity https://doi.org/10.47248/chp2603020007

Received: Jun 19, 2026 | Accepted: Jun 19, 2026 | Published: Jun 22, 2026