Immune escape is one of the important features of cancer progression and a core challenge that affects the effectiveness of immunotherapy. Although immune checkpoint inhibitors (ICI) have achieved significant success in certain cancers, the overall response rate in solid tumors is still very limited. Exploring the mechanism of tumor immune escape in depth, discovering new targets, and improving ICI efficacy through combination therapy have become one of the key directions of current tumor immune research.

On September 19, 2024, Professor Jiang Kuirong and Professor Feng Xu from the First Affiliated Hospital of Nanjing Medical University, together with Professor Chen Junjie and Professor Jiang Dadi from the MD Anderson Cancer Center of the University of Texas in the United States, published a research paper entitled In vivo CRISPR screens identify Mga as an immune target in triple negative breast cancer online on PNAS magazine, systematically expounded the core route of immune escape in various tumor types, focused on triple negative breast cancer, and revealed the key role of MGA in its immune escape. Related molecular mechanisms.

In this study, the team used CRISPR screening technology in vivo. First, the whole genome library was used to preliminarily screen the homologous tumor xenotransplantation mouse models of colon cancer (MC38) and breast cancer (EMT6); According to the preliminary screening results, we designed and synthesized a small focused library (named murine putative immune modulators library, mPIM), which was expanded to seven homologous tumor models in the second round of validation screening, covering five cancer types, namely, breast cancer, colon cancer, melanoma, prostate cancer and ovarian cancer. Through iterative screening, the team discovered a series of highly credible immune escape genes and their possible functional associations in different models. In addition to the immune escape genes that have been extensively studied in recent years, such as interferon gamma signaling pathway and antigen processing and presentation related genes, more importantly, a series of new genes involved in tumor immune escape were revealed, which can serve as potential new targets for immune combination therapy. The study specifically focused on TNBC and found that Mga (Max's giant associated protein) is a specific immune regulatory target for TNBC. Its absence can enhance anti-tumor immune response and inhibit the growth of TNBC in immunocompetent mice. Transcriptome and single-cell RNA sequencing analysis further revealed that Mga can affect the tumor immune microenvironment by regulating multiple immune related pathways such as MHC-II. In line with this, the analysis of TCGA breast cancer patient data shows that the low expression of MGA is associated with better prognosis, especially in patients with high expression of interferon - g. This discovery provides a novel potential target for immune combination therapy of TNBC, but the role of Mga as a multifunctional transcriptional regulator in tumor immunity still needs further exploration to fully elucidate its regulatory network and therapeutic potential.