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<p>The ubiquitin–proteasome system generates peptide fragments that are displayed on class I major histocompatibility complex molecules. Hapten-modified peptides, or covalent neoantigens, arise from proteins covalently modified by small molecules and have long been proposed as components of a mechanism for immune recognition. Here we report a platform to investigate this mechanism and harness covalent neoantigens for immune cell recruitment and activation. Using cysteine-reactive probes, we demonstrated that covalently modified intracellular proteins could be processed and presented as covalent neoantigens in multiple cell lines. Immunopeptidomics confirmed the presence of probe-modified peptides within the class I major histocompatibility complex immunopeptidome. We further developed a bioorthogonal strategy for immune cell engagement by combining covalent neoantigens bearing a bioorthogonal handle with complementary immune cell recruiters, leading to activation of CD32- and CD3-expressing reporter immune cells. These findings expand the scope of covalent neoantigen formation and provide a generalizable strategy for immune targeting of covalent neoantigens.</p><p></p>

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Expanding the repertoire of chemically induced covalent neoantigens

  • 期刊论文

  • 发表日期：

    2026年7月30日

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  • Chen Zhou,
  • Xiaokang Jin,
  • Wei Huang,
  • Haofeng Wu,
  • Lynn M. McGregor,
  • Markus Schirle,
  • Chenlu Zhang,
  • Xiaoyu Zhang

摘要

The ubiquitin–proteasome system generates peptide fragments that are displayed on class I major histocompatibility complex molecules. Hapten-modified peptides, or covalent neoantigens, arise from proteins covalently modified by small molecules and have long been proposed as components of a mechanism for immune recognition. Here we report a platform to investigate this mechanism and harness covalent neoantigens for immune cell recruitment and activation. Using cysteine-reactive probes, we demonstrated that covalently modified intracellular proteins could be processed and presented as covalent neoantigens in multiple cell lines. Immunopeptidomics confirmed the presence of probe-modified peptides within the class I major histocompatibility complex immunopeptidome. We further developed a bioorthogonal strategy for immune cell engagement by combining covalent neoantigens bearing a bioorthogonal handle with complementary immune cell recruiters, leading to activation of CD32- and CD3-expressing reporter immune cells. These findings expand the scope of covalent neoantigen formation and provide a generalizable strategy for immune targeting of covalent neoantigens.