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Expanding the repertoire of chemically induced covalent neoantigens

ABSTRACT: The ubiquitin-proteasome system (UPS) generates peptide fragments that are displayed on class I major histocompatibility complex (MHC-I) molecules. Hapten-modified peptides, which are derived from proteins covalently modified by exogenous small molecules, have long been proposed as a mechanism for immune recognition. Building on this concept, recent studies have begun to harness this mechanism for therapeutic purposes, demonstrating that covalent small molecules can engage this pathway to drive the presentation of hapten-modified peptide fragments, or covalent neoantigens. Here, we report a platform to systematically investigate this process and harness covalent neoantigens for immune cell recruitment and activation. Using bioorthogonal cysteine-reactive probes, we demonstrate that covalently modified intracellular proteins can be processed and presented as covalent neoantigens in multiple cell lines. Immunopeptidomics confirmed the presence of probe-modified peptides within the MHC-I immunopeptidome. We further integrated a bioorthogonal strategy for immune cell engagement by pairing methyltetrazine (mTz)-tagged covalent neoantigens with trans-cyclooctene (TCO)-conjugated immune cell recruiters, leading to the activation of CD32- and CD3-expressing reporter immune cells. These findings indicate an expanded scope of covalent neoantigen formation and provide a generalizable strategy for immune targeting of covalent neoantigens.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Xiaoyu Zhang

LAB HEAD: Xiaoyu Zhang

PROVIDER: PXD077352 | Pride | 2026-07-08

REPOSITORIES: Pride

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			Action	DRS
	SEARCH.txt	Txt
	Table_S1_IAmTz_treated_lysates_rep1.raw	Raw
	Table_S1_IAmTz_treated_lysates_rep2.raw	Raw
	Table_S1_Raji_rep1.raw	Raw
	Table_S1_Raji_rep2.raw	Raw

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