Two recent studies, by Ely et al. and Apavaloaei et al., revealed that non-canonical antigens derived from unmutated, noncoding regions dominate the immunopeptidome of many cancers. Here, we discuss how this challenges conventional mutation-centric immunotherapies and highlight emerging strategies, including cryptic antigen- and TCR-targeted vaccines, as promising new clinically relevant paths in personalised and off-the-shelf cancer immunotherapy.

N6-methyladenosine (m6A) is a key mRNA modification influencing mRNA stability and translation. YTHDF2, a major m6A ‘reader’, was initially recognized for promoting mRNA decay but is now also known to enhance translation by binding to methylated mRNAs. YTHDF2 maintains the function of immune suppressive cells, including tumor-associated macrophages (TAMs), myeloid-derived suppressor cells (MDSCs), and regulatory T cells (Tregs), while also supporting cytotoxic immune cells, including natural killer (NK) and CD8+ T cells. Additionally, YTHDF2 acts as a tumor-intrinsic regulator orchestrating tumor immune evasion. Its multifaceted roles in tumor immunity make YTHDF2 a promising yet challenging therapeutic target. This review explores the complex roles and mechanisms of YTHDF2 in cancers, immune regulation, and tumor immune evasion and highlights emerging therapeutic strategies that target YTHDF2.

Proteins with a Toll/interleukin-1 receptor/resistance (TIR) domain are among the most ancient immune regulators and include well-known pattern recognition receptors (PRRs). A specialized subset of TIR domain proteins are enzymes that predominantly use nicotinamide adenine dinucleotide (NAD+) to generate second messenger metabolites. These enzymatic TIR proteins have essential roles in bacteria, plant, and animal immunity. The mechanism of activation of these TIR proteins, conserved across Kingdoms, involves oligomerization into higher-ordered structures, which activates their intrinsic enzymatic activity. Here, we review the functions of enzymatic TIR proteins in innate immunity in bacteria, plants, and animals. This work offers insights into the evolutionary origins of immunity itself and defines fundamental principles of immune surveillance across the Tree of Life.