Tumor-intrinsic YTHDF1 drives immune evasion and resistance to immune checkpoint inhibitors via promoting MHC-I degradation

Abstract

The recently described role of RNA methylation in regulating immune cell infiltration into tumors has attracted interest, given its potential impact on immunotherapy response. YTHDF1 is a versatile and powerful m6A reader, but the understanding of its impact on immune evasion is limited. Here, we reveal that tumor-intrinsic YTHDF1 drives immune evasion and immune checkpoint inhibitor (ICI) resistance. Additionally, YTHDF1 deficiency converts cold tumors into responsive hot tumors, which improves ICI efficacy. Mechanistically, YTHDF1 deficiency inhibits the translation of lysosomal genes and limits lysosomal proteolysis of the major histocompatibility complex class I (MHC-I) and antigens, ultimately restoring tumor immune surveillance. In addition, we design a system for exosome-mediated CRISPR/Cas9 delivery to target YTHDF1 in vivo, resulting in YTHDF1 depletion and antitumor activity. Our findings elucidate the role of tumor-intrinsic YTHDF1 in driving immune evasion and its underlying mechanism.

CRISPR/Cas9 Genome Editing for Tissue‐Specific In Vivo Targeting: Nanomaterials and Translational Perspective

“…When injected intratumorally, this CRISPR/Cas9 plasmids targeting YTHDF1 gene efficiently reduced tumorigenesis in tumor bearing C56BL/6J mice. [140] Similarly, Luo et al used AML12-cell-derived exosomes which are safe and effective to deliver CRISPR/dCas9-VP64 to the hepatic stellate cells which contribute significantly to liver fibrosis. This resulted in the effective delivery of the CRISPR/Cas9 tool effectively into the hematopoietic stem cells (HSCs) both in vitro and in vivo and enhanced the reprogramming of HSCs to hepatocyte phenotype.…”

CRISPR/Cas gene editing and delivery systems for cancer therapy

“…Exosome RNP facilitated accumulation in the liver tissue and effective gene editing targeted gene, which resulted in satisfying therapeutic effects on orthotopic HCC mouse models. Lu and co-workers utilized exosomes derived from B16F10 tumor tissue via ultra-centrifugation to load CRISPR/Cas9 plasmids targeting Ythdf1 gene through professional kit (Lin et al, 2023). The exosomes showed efficient tumor targeting after intratumoral injection, apparently depleted the expression of Ythdf1, greatly suppressed the growth of B16F10 tumors, and elicited robust anti-tumor immunity without obvious toxicity.…”

KCl Nanoparticles as Potential Inducer of Immunogenic Cell Death for Cancer Immunotherapy

“…21,22 Meanwhile, tumor immunotherapy also faced the challenges of the toxicity of chemotherapy agents, the biosafety of ICD inducers and the compatibility of nanocarriers loaded with drugs. 23,24 All of the above factors lead to the antitumor immune response effect seeming to be less than expected. 25 Hence, it is urgent to develop an antitumor immune response strategy with precise targeting ability, low systemic toxicity, and high efficiency.…”

“…Cancer immunotherapy, which inhibits the development of cancer by activating the patient’s immune system, has demonstrated great therapeutic potential in the treatment of cancer. − Immunogenic cell death (ICD) as a fundamental tumor immunotherapy approach has been studied extensively. − ICD is accompanied by releasing of tumor-associated antigens and a large number of damage-associated molecular patterns (DAMPs), which can induce dendritic cell (DC) maturation to enhance cancer immunotherapy. − Recently, various ICD inducers have been developed, such as classic chemotherapy drugs (doxorubicin), , photosensitizers (iron-based metal–organic frameworks, MOFs), photothermal therapy initiators (gold nanoparticles, AuNPs), − and sonodynamic therapy inducers (such as TiO 2 ). , However, the complex immunosuppressive tumor microenvironment (ITM) leads to low antigen delivery efficiency and limited immunogenicity. , Meanwhile, tumor immunotherapy also faced the challenges of the toxicity of chemotherapy agents, the biosafety of ICD inducers and the compatibility of nanocarriers loaded with drugs. , All of the above factors lead to the antitumor immune response effect seeming to be less than expected . Hence, it is urgent to develop an antitumor immune response strategy with precise targeting ability, low systemic toxicity, and high efficiency.…”