Transforming cancer treatment: integrating patient-derived organoids and CRISPR screening for precision medicine

Abstract

The persistently high mortality rates associated with cancer underscore the imperative need for innovative, efficacious, and safer therapeutic agents, as well as a more nuanced understanding of tumor biology. Patient-derived organoids (PDOs) have emerged as innovative preclinical models with significant translational potential, capable of accurately recapitulating the structural, functional, and heterogeneous characteristics of primary tumors. When integrated with cutting-edge genomic tools such as CRISPR, PDOs provide a powerful platform for identifying cancer driver genes and novel therapeutic targets. This comprehensive review delves into recent advancements in CRISPR-mediated functional screens leveraging PDOs across diverse cancer types, highlighting their pivotal role in high-throughput functional genomics and tumor microenvironment (TME) modeling. Furthermore, this review highlights the synergistic potential of integrating PDOs with CRISPR screens in cancer immunotherapy, focusing on uncovering immune evasion mechanisms and improving the efficacy of immunotherapeutic approaches. Together, these cutting-edge technologies offer significant promise for advancing precision oncology.

Keywords: CRISPR screening; cancer treatment; immunotherapy; patient-derived organoids; precision medicine.

FIGURE 1

Integration of PDOs and functional CRISPR screens. Functional screening in organoids can be realized via CRISPR-Cas screening technologies, including CRISPR KO, CRISPRa, and CRISPRi. After screening for phenotypes, bioinformatics prediction and screening are utilized to identify phenotype-associated genes, drug resistance genes and TSGs as potential therapeutic targets to reverse drug resistance or in combination with drugs provides new methods for cancer treatment and research, including identifying key genetic drivers of cancer and potential therapeutic targets, improving the drug screening process, and enhancing patient prognosis.

FIGURE 2

Using CRISPR screens in cancer organoids to identify different cancer therapeutics. CRISPR screens for drugs in different cancer PDOs, such as chemotherapy agents (A), targeted drugs (B), and RNA-based therapeutics (C), which in combination with potential therapeutic targets in the screened tumors can reverse resistance or combine them to further improve drug efficacy.

FIGURE 3

Using CRISPR screens in PDOs for cancer treatment strategies. (A) Targeting tumor cell death. The role of phenotype related genes and drugs in tumor cell death mechanism, including inhibition of cell proliferation (e.g., CDK12, EHMT1/2, and ITGB1), and induction of cell death (e.g., HMOX1 and DOCK1). (B) Therapeutic implications. By incorporating immune cells into PDO culture, followed by CRISPR screening to assess the efficacy of drug therapy and identify the immunotherapy targets.