Preferential activation of type I interferon-mediated antitumor inflammatory signaling by CuS/MnO2/diAMP nanoparticles enhances anti-PD-1 therapy for sporadic colorectal cancer.

Converting the "cold" tumor microenvironment (TME) to a "hot" milieu has become the prevailing approach for enhancing the response of immune-excluded/immunosuppressed colorectal cancer (CRC) patients to immune checkpoint blockade (ICB) therapy. During this process, inflammation accompanied by different kinds of chemokines/cytokines inevitably occurs. However, some activated inflammatory signals exhibit protumor potency. Therefore, strategies that preferentially activate antitumor inflammatory signaling rather than tumor-promoting signaling need to be developed. Herein, we constructed a STING agonist-loaded CuS/MnO₂ bimetallic nanosystem, termed diAMP-BCM. BCM with an optimized Cu/Mn ratio efficiently promoted the activation of proinflammatory signaling, and in combination with the STING agonist diAMP, diAMP-BCM controllably activated tumoricidal inflammatory signaling in APCs. DiAMP-BCM can efficiently generate ROS and promote the activation of STING, which induces the apoptosis of cancer cells and promotes the recruitment of monocytes while facilitating the polarization of macrophages and maturation of DCs. MC38 and CT26 CRC models were established to evaluate the in vivo antitumor effects of diAMP-BCM. Combined with ICB therapy, diAMP-BCM enables the rebuilding of tumor milieus with efficient tumor growth inhibition and alleviation of T-cell exhaustion, particularly in distal tumors, in sporadic colorectal cancer therapy. This study established a nanoplatform to promote the preferential activation of antitumor inflammatory signaling, rebuild the T-cell repertoire and alleviate T-cell exhaustion to enhance cancer ICB immunotherapy.