Targeting hypoxia-mediated chemo-immuno resistance by a hybrid NBDHEX-Pt(IV) prodrug via declining nuclear STING1-promoted AhR-CIN in human lung squamous cell carcinoma

As found in human lung squamous cell carcinoma (LUSC), STING1 involved in ER-Golgi intermediate compartment (ERGIC) could coordinate immune responses to ectopic DNA triggered by DNA-targeted chemotherapy. ERGIC STING1 is considered to compete with nuclear STING1 to decline aryl hydrocarbon receptor (AhR)-chromosomal instability (CIN)-triggered chronic STING activation which could cause therapeutic resistance. Moreover, GSTP1 was proved to inhibit ERGIC-STING1 via promoting S-glutathione modification of STING1. Hence, a potent GSTP1-targeted Pt(IV) hybrid NBDHEX-DN604, was designed via conjugating a GSTP1 inhibitor NBDHEX to the axial position of Pt(IV) prodrug. As mentioned, hypoxia is mainly observed in malignant tumors and develops acquired drug resistance. In vitro bio-properties of hypoxic SK-MES-1/cDDP cells demonstrated that NBDHEX-DN604 could reverse chemo-immuno resistance via intercepting GSTP1 to activate ERGIC STING1, leading to the decrease of nuclear STING1. The mechanistic data indicated that NBDHEX-DN604 could elevate ERGIC STING1 to mitigate nuclear STING1-mediated AhR-TLS-CIN-chronic activation. Meanwhile, NBDHEX-DN604 was found to decline STING1-AhR-CIN to circumvent chemo-immuno resistance, resulting in predominant in vivo antitumor effect in HY-KLN-205/cDDP-inoculated BALB/c mice. The data provide a novel rationale for the mixed chemo-immunotherapy of NBDHEX-DN604 as a potent Pt(IV) therapeutic method for patients with resistant LUSC.