The allogenic non-proteinogenic amino acid BMAA-based vaccine breaks up the immune tolerance against colorectal cancer

作者：Baorui Tian, Shijian Wang, Jixuan Ding, Wang Qu, Chen Zhang, Fuxin Luan, Nan Wang, Yigong Hou, Mengying Suo, Huimin Liu, Yanan Chen, Yanhua Liu, Jie Yan, Jianbo Zhang, Lee Jia, Longlong Wang, Yi Shi, Rong Xiang · 发表于：Theranostics · 年份：2025 · DOI：10.7150/thno.104722 · 被引用次数：6 · 研究领域：Immunotherapy and Immune Responses、Immune Cell Function and Interaction、Cancer Immunotherapy and Biomarkers

The fundamental issue in immunotherapy is the lack of tumor-specific antigens in most types of tumors, leading to immune tolerance.For approximately 85% of patients with microsatellite stable (MSS) colorectal cancer (CRC), the absence of tumor neoantigens results in poor immunotherapy efficacy.Our previous study demonstrated that the misincorporation of non-proteinogenic proline (Pro) analog azetidine-2-carboxylic acid (AZE) could generate mutated proteins that significantly enhance tumor cell antigenicity and anti-tumor immune responses.Methods: To activate more specific anti-tumor immune responses with fewer side effects, we utilized the non-proteinogenic serine (Ser) analog β-N-methylamino-L-alanine (BMAA), which can be misincorporated into proteins as a Ser substitute by seryl tRNA synthetase at an appropriate rate.BMAA misincorporated neoantigens were detected using mass spectrometry (MS), and cancer cell-enriched peptides with high antigenicity were selected in a murine CRC model for the preparation of BMAA-based self-assembling nanoparticles (SAN).Single-cell sequencing was performed to analyze immune responses induced by SAN vaccination combined with a toll-like receptor 7 agonist (TLRa) adjuvant and BMAA treatment.Results: SAN-TLRa vaccination with BMAA treatment induced an anti-tumor immune microenvironment.This combination stimulated the generation of specific CD8 + T cells and IgG targeting BMAA misincorporated neoepitopes, ultimately promoting immune activation, ...