Uncovering spatially resolved functional genomics with CRISPR screen sequencing

Haorui Zhang; Zongxu Zhang; Peiyu Wang; Tian Xu; Xiaoyu Chen; Yanping Zhao; Siyu Lin; Wenjie Cai; Pengfei Ren; Ce Luo; Peng Zhang; Yunfeng Wang; Sen Hou; Yahui Zhao; Hu Zeng; Zhihua Liu; Cunyu Wang; Zhidong Gao; Yu Feng; Deng Pan; Zexian Zeng

doi:10.1016/j.cell.2026.04.049

Uncovering spatially resolved functional genomics with CRISPR screen sequencing

Cell. 2026 May 26:S0092-8674(26)00516-7. doi: 10.1016/j.cell.2026.04.049. Online ahead of print.

Authors

Haorui Zhang¹, Zongxu Zhang², Peiyu Wang³, Tian Xu³, Xiaoyu Chen⁴, Yanping Zhao⁵, Siyu Lin¹, Wenjie Cai¹, Pengfei Ren³, Ce Luo¹, Peng Zhang¹, Yunfeng Wang³, Sen Hou⁶, Yahui Zhao⁷, Hu Zeng¹, Zhihua Liu⁷, Cunyu Wang⁸, Zhidong Gao⁶, Yu Feng⁹, Deng Pan¹⁰, Zexian Zeng¹¹

Affiliations

¹ Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100084, China.
² Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100084, China.
³ Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100084, China; Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100084, China.
⁴ BGI Research, Hangzhou 310030, China.
⁵ Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
⁶ Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100084, China.
⁷ State Key Laboratory of Molecular Oncology, National Cancer Center, National Clinical Research Center for Cancer, Cancer Hospital, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing 100021, China.
⁸ Beijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Institute of Advanced Clinical Medicine, Peking University, Beijing 100871, China.
⁹ State Key Laboratory of Genome and Multi-omics Technologies, BGI Research, Shenzhen 518083, China; BGI Collaborative Center for Future Medicine, Shanxi Medical University, Taiyuan 030001, China. Electronic address: fengyu1@genomics.cn.
¹⁰ School of Basic Medical Sciences, Tsinghua University, Beijing 100084, China; Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing 100084, China. Electronic address: dpan@tsinghua.edu.cn.
¹¹ Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100084, China; Center for Quantitative Biology, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100084, China; Peking University Chengdu Academy for Advanced Interdisciplinary Biotechnologies, Chengdu 610213, Sichuan, China. Electronic address: zexianzeng@pku.edu.cn.

PMID: 42190664
DOI: 10.1016/j.cell.2026.04.049

Abstract

Spatial omics has advanced our understanding of tissue-level biology, yet tools to systematically link gene functional perturbations to spatial phenotypes and signaling pathways remain limited. To address this, we developed spatial CRISPR screen sequencing (SPAC-seq), a high-throughput spatial CRISPR screen platform, and TARDIS (target prioritization toolkit for perturbation data in spatial omics), a statistical spatial perturbation analysis toolkit. Using SPAC-seq and TARDIS, we linked gene perturbations to spatial phenotypes and pathways, uncovering how Icam1 loss in tumor cells promotes metastasis via immune suppression and macrophage polarization. In CD8⁺ T cells, we revealed Cd44's role in regulating spatial phenotypes by interacting with Spp1 on macrophages. We also demonstrated the model of the transcription factor-chemokine receptor axis coupling cell states with chemotaxis. SPAC-seq and TARDIS provide an effective framework to study spatially resolved functional genomics and pathways across diverse biological and disease contexts.

Keywords: Cd44; Icam1; Spp1; cancer immunology; in vivo CRISPR screen; spatial CRISPR screen; spatial genomics; spatial perturbation analysis toolkit; spatial sequencing technology; spatial transcriptomics.