Nowadays, tumor immunotherapies have achieved unprecedented therapeutic effects in the treatment of cancer [1]. Accumulating evidences indicate that tumor immunotherapies intrinsically depend on the specific triggering of T cells by neoantigens, and the quantity and quality of neoantigens are likely to be the core factors affecting the immunotherapeutic effect of cancers [2]. Neoantigens are essentially MHC-I presented short peptides, which are mainly arised from proteasome-degraded mutant proteins. Although a large number of somatic mutations existed in tumor cells, neoantigens are still scarce. Notably, the generation of neoantigens can be regulated. Lu et al. [3] found that enriching neoantigens of cancers by regulating the mRNA splicing process can trigger anti-tumor T cell response or enhance checkpoint immunotherapy to inhibit tumor growth. This discovery indicated that effective positive regulation of tumor immunotherapies can be achieved by increasing the abundance of neoantigens. However, this strategy lacks tumor specificity. Additionally, Fidanza et al. [4] regulated the degradation process of the vaccine in proteasome by designing a single tyrosine substitution (Y6 PepVIII) to strengthen the cellular anti-tumor immune response and increase the survival rate of mice, which implies that regulating the degradation of mutant proteins may be another effective way to enrich tumor neoantigens.

Interestingly, there have been some studies verifying the possibility and correctness of the conjecture. One research utilized a PROTAC named Datg-7 to induce the degradation of fusion protein including FKBP12F36V and OVA peptide by the proteasome, therefore increasing the OVA peptide presentation on MHC-I, and they first discovered that PROTAC had a new immune-stimulating characteristic. What’s more, the fact that mature or stable antigens can serve as an important source of peptides feeding the MHC-I presentation pathway was also demonstrated in this study [8]. Jensen et al. [9] also found that ARV-825 (JQ1-CRBN), ARV-771 (JQ1-VHL), and JQ1-MDM2 promoted the presentation of bromo- and extra terminal domain (BET) peptides. But it is still not apparent if the change in MHC-I peptide quantity caused by degraders is adequate to activate T cells killing tumor cells. Then another research answered this question. Massafra et al. increased the presentation of antigenic BRD4 peptides shown on MHC-I by corresponding BRD4 PROTAC. Furthermore, they also revealed that the effect of PROTAC-dependent degradation on the increase of antigens presentation is sufficient to trigger the immune response against cancer cells for the first time. To draw this conclusion, they explored the biological justification for combining a degrader and an antigen-directed immunotherapeutic for oncology purposes in a coculture model of cancer cells and T cells [10].

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