Cancer genomics collectively aims to chart the molecular drivers underlying the cancer progression, understand the biological basis of tumor heterogeneity, and, accordingly, provide personalized therapeutic strategies. In the past 20 years, benefitting from the continuous improvements of high-throughput sequencing technologies, we have witnessed the rapid development of cancer genomics, which drives a revolution in cancer biology with an expanded knowledge of not only cancer cells per se but also the holistic tumor microenvironment. Such achievements have greatly advanced rational therapeutic interventions.

　　Prof. Zemin Zhang, the director of the Biomedical Pioneering Innovation Center (BIOPIC), has recently been invited to publish a review article titled "Accelerating the understanding of cancer biology through the lens of genomics " in Cell , which summarizes the major milestones of cancer genomics and highlights its critical contribution to deciphering the cancer-driving events, understanding tumor heterogeneity, and promoting personalized precision medicine. The paradigm shift of cancer genomics, elevating from the focus on the characteristics of cancer cells themselves to studying the holistic tumor "ecosystem", has been emphasized. Finally, the article also discusses potential future frontiers in advancing the development of fundamental cancer biology as well as clinical transformation applications.

　　This review first highlights the milestone discoveries of cancer genomics on carcinogenic mechanisms, tumor stratification, and precision medicine. In 2010, Prof. Zemin Zhang has led the sequencing of the first whole-genome of the human solid tumor, enabling the study of different types of oncogenic mutations at the genome-wide scale [1]. Tumor stratification based on driver mutations promotes the development of targeted precision therapies, with examples including non-small cell lung cancer patients with EGFR mutations and melanoma patients with BRAF mutations, which can respond to their corresponding targeted drugs, respectively. The international consortia, including TCGA and ICGC, have deciphered driver genes and molecular subtypes for most major cancer types by integrating large-scale, multi-omics measurements. The article then emphasizes three technical factors – sample size, measurement dimensions, and resolution – for the further development of cancer genomics studies.

　　Tumor heterogeneity seriously hinders the efficacy of cancer therapies, and understanding the molecular heterogeneity within tumors is thereby one central theme of cancer genomics. Although traditional bulk samples have revealed intertumoral heterogeneity among patients, accurately identifying intratumoral heterogeneity within samples can be challenging. In 2012, an early study applied multiregional sampling to analyze the intratumoral spatial heterogeneity, recognizing a substantial portion of driver mutations specific to certain but not all assayed regions. Promisingly, the development of single-cell whole-genome sequencing technologies, such as LIANTI [2], has provided novel opportunities for investigating intratumoral heterogeneity. We can now track the evolutionary history of cancer cells and the intratumoral distribution of oncogenes at the single-cell level, opening new possibilities for addressing the drug resistance of cancer patients.

　　Immune checkpoint blockade (ICB) was officially approved by the FDA first in 2011 and has exhibited remarkable success in clinical settings. Aside from the study of cancer cell heterogeneity, investigating the characteristics and heterogeneity of the holistic tumor ecosystem, especially the immune microenvironment, has emerged as a new direction for cancer genomics research. Single-cell whole-transcriptome sequencing, first available in 2009, offers technological support for comprehensively characterizing the composition and functional states of the tumor microenvironment. The team of Prof. Zemin Zhang has since pioneered the single-cell level study of the tumor immune microenvironment, uncovering the multifaceted characteristics of tumor-infiltrating T and myeloid cells, including their functional status, components, evolutionary trajectories, cellular interactions, and heterogeneity, in liver cancer, lung cancer, colorectal cancer, respectively, and further at the pan-cancer level (Figure 1) [4,5,6,7]. They have identified a variety of tumor-specific immune cell types, such as CXCL13+ T cells, SPP1+ tumor-associated macrophages, and LAMP3+ dendritic cells, and explained their association with patient prognosis and ICB response, promoting the full understanding of the heterogeneity of the tumor ecosystem.

　　Figure 1 Characterization of the tumor microenvironment

　　Cancer genomics is currently experiencing rapid development. With the accumulation of single-cell sequencing data, large-scale integration is becoming accessible to perform patient stratification based on the characteristics of their tumor microenvironments, providing new opportunities for precise immunotherapy strategies. Meanwhile, the emerging advanced technologies, such as spatial genomics, single-cell multi-omics, and CRISPR screening coupled with single-cell transcriptomes as readouts, would further enrich our understanding of the composition and functional mechanisms of the tumor microenvironment. In the next few years, cancer genomics is expected to make critical breakthroughs in cancer biology as well as clinical transformations. With the support of international consortia, such as HCA and HTAN, we will gradually decipher the truly complete composition and cellular interactions of human tumors, and comprehensively understand the spatiotemporal dynamic changes spanning the whole history of cancer development and treatment. In addition, the early causal events of the tumor ecosystem would be pinpointed, with the time point of malignant transformation identified and the influencing factors determining the branch of different types of tumor microenvironments recognized. Furthermore, the application of liquid biopsy for non-invasive detection of the tumor microenvironment status, combined with genomics methods, will assist in the early detection and treatment of cancer.

　　As the perspective expands to the holistic tumor ecosystem, this article highlights a new paradigm for developing cancer treatment strategies. Compared with traditional targeted therapies which focus on the intrinsic signaling pathways of cancer cells and kill cancer cells by interfering with "target genes", the article proposes the "target cell" theory of cancer treatment (Figure 2), in which complex cellular interactions are central to multifaceted immunosuppressive mechanisms, and certain regulatory cell types can be specifically perturbed to favor anti-tumor immunity or even eradicate tumors. Through blocking cancer immune evasion mechanisms that are still unknown or not effectively intervened, and enhancing the ability of the immune system to kill cancer cells, the approach of "target cells" is expected to expand current immune checkpoint inhibition therapies and provide new prospects for cancer treatment.

　　Figure 2 Discovering new cancer treatment options based on "target cells"

　　Dr. Dongfang Wang and Ph.D. candidate Baolin Liu from BIOPIC are the co-first authors of the article, and Prof. Zhang Zemin is the corresponding author. This work was supported by the National Natural Science Foundation of China, the Beijing Municipal Science and Technology Commission, the Beijing Advanced Innovation Center for Genomics (ICG), and the Changping Laboratory.

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