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  • Unraveling the Cellular and Spatial Heterogeneity of Ocular Cancers through Single-Cell and Spatial Omics

  • Delnia Khadiry,1,* Zahra Nasrollahi ,2
    1. Kermanshah University of Medical Science
    2. Kermanshah University of Medical Science


  • Introduction: Ocular malignancies, most notably uveal melanoma (UM) and retinoblastoma (RB), are characterized by profound molecular and cellular diversity. This heterogeneity is a primary driver of tumor progression, metastatic spread, and the development of therapeutic resistance. While traditional bulk transcriptomics provide an average molecular profile, they often fail to capture the rare cell subpopulations and the intricate communication within the tumor microenvironment (TME) that dictate clinical outcomes. The emergence of single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics has revolutionized our ability to map these complexities at high resolution.In UM, these technologies have uncovered distinct malignant states and specialized immune cell subsets—such as heterogeneous macrophage and T-cell populations—that drive aggressive phenotypes. Similarly, spatial transcriptomics in RB has shown that molecularly divergent tumor subtypes can coexist within the same histological landscape. By integrating single-cell and spatial insights, we aim to better understand the cellular mechanisms governing immune evasion and metastasis in ocular cancers.
  • Methods: A systematic literature search was conducted using the PubMed database, focusing on studies published between 2015 and 2026. The search was specifically targeted toward advancements in single-cell and spatial omics within the context of ocular cancers. After a rigorous screening process, seven high-impact studies were selected for this review. The selection criteria were centered on the studies’ ability to provide direct mechanistic insights into intratumoral heterogeneity, tumor–immune interactions, and the processes driving metastatic progression. Studies that lacked specific spatial or single-cell mechanistic data were excluded to ensure a high resolution of analysis.
  • Results: Our synthesis of the selected literature highlights several key mechanisms driving ocular cancer evolution. In primary uveal melanoma, scRNA-seq data identified specific transcriptional states within a single tumor, notably an invasive subpopulation driven by HES6 activity. Experimental evidence suggests that HES6 plays a pivotal role in promoting tumor growth, motility, and eventual metastatic dissemination. Furthermore, analysis of UM liver metastases underscored significant intra- and intertumoral variability, ranging from distinct copy-number alterations to divergent proliferative and migratory phenotypes.The immune landscape of UM also demonstrated remarkable complexity. We identified specialized macrophage subsets, such as the MΦ-C4 population, which correlates with immune suppression and diminished clinical prognosis. The metastatic environment of UM further revealed a highly diverse pool of tumor-reactive lymphocytes, exhibiting a spectrum of activated, exhausted, memory, and cytotoxic states.A critical finding involves the direct crosstalk between neoplastic and immune cells. The identification of “hybrid” tumor-immune cells—which express both malignant and macrophage-associated programs—suggests a sophisticated method of immune evasion and metabolic reprogramming (including actin remodeling and EMT) that facilitates metastasis. Additionally, the presence of a specific spp1+ melanoma subpopulation, which appears to interact with ccl3+ macrophages, points toward a potential tumor–macrophage axis that triggers early metastatic events.In the context of retinoblastoma, spatial transcriptomics provided a physical map of this molecular diversity. The data revealed that well-differentiated and poorly differentiated regions possess distinct transcriptional profiles (related to photoreceptor differentiation and cell proliferation, respectively) that coexist within the same tumor architecture, confirming that molecular heterogeneity is spatially organized.
  • Conclusion: Current evidence from single-cell and spatial omics indicates that ocular cancer progression is not a uniform process but is fueled by highly specialized and heterogeneous cellular interactions. In UM, the interplay between invasive tumor subpopulations, diverse immune cells, and hybrid tumor–immune entities appears to facilitate metastasis through coordinated shifts in metabolism and immune evasion. The spp1+ The tumor-macrophage axis represents a particularly promising area for understanding early metastatic spread. Moreover, the spatial mapping in RB confirms that molecular subtypes are intrinsically linked to the tumor’s physical structure. Ultimately, these high-resolution omics approaches are essential for identifying novel biomarkers and therapeutic targets tailored to the specific cellular landscape of ocular malignancies.
  • Keywords: Uveal Melanoma, Single-Cell RNA Sequencing, Spatial Transcriptomics

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