Mn-based cGAS-STING activation for tumor therapy

Immunotherapy has efficiently revolutionized the treatment of human neoplastic diseases. However, the overall responsive rate of current immunotherapy is still unsatisfactory, benefiting only a small proportion of patients. Therefore, significant attention has been paid to the modulation of tumor microenvironment (TME) for the enhancement of immunotherapy. Interestingly, recent studies have shown that cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) was initially found as an innate immune sensor to recognize cytoplasmic DNA (such as bacterial, viral, micronuclei, and mitochondrial). It is a promising signaling pathway to activate antitumor immune responses via type I interferon production. Notably, Mn²⁺ was found to be a critical molecule to sensitize the activation of the cGAS-STING pathway for better immunotherapy. This activation led to the development of Mn²⁺-based strategies for tumor immunotherapy via the activation of the cGAS-STING pathway. In this critical review, we aimed to summarize the recent progress of this field, focusing on the following three aspects. First, we briefly introduced the signaling pathway of cGAS-STING activation, and its regulation effect on the antitumor immunity cycle has been discussed. Along with this, several agonists of the cGAS-STING pathway were introduced with their potential as immunotherapeutic drugs. Then, the basic biological functions of Mn²⁺ have been illustrated, focusing on its critical roles in the cGAS-STING pathway activation. Next, we systematically reviewed the Mn²⁺-based strategies for tumor immunotherapy, which can be classified by the methods based on Mn²⁺ alone or Mn²⁺ combined with other therapeutic modalities. We finally speculated the future perspectives of the field and provided rational suggestions to develop better Mn²⁺-based therapeutics.