A cooperative nano-CRISPR scaffold potentiates immunotherapy via activation of tumour-intrinsic pyroptosis

Abstract

Efficient cancer immunotherapy depends on selective targeting of high bioactivity therapeutic agents to the tumours. However, delivering exogenous medication might prove difficult in clinical practice. Here we report a cooperative Nano-CRISPR scaffold (Nano-CD) that utilizes a specific sgRNA, selected from a functional screen for triggering endogenous GDSME expression, while releasing cisplatin to initiate immunologic cell death. Mechanistically, cascade-amplification of the antitumor immune response is prompted by the adjuvantic properties of the lytic intracellular content and enhanced by the heightened GDSME expression, resulting in pyroptosis and the release of tumor associated antigens. Neither of the single components provide efficient tumour control, while tumor growth is efficiently inhibited in primary and recurrent melanomas due to the combinatorial effect of cisplatin and self-supplied GSDME. Moreover, Nano-CD in combination with checkpoint blockade creates durable immune memory and strong systemic anti-tumor immune response, leading to disease relapse prevention, lung metastasis inhibition and increased survival in mouse melanomas. Taken together, our therapeutic approach utilizes CRISPR-technology to enable cell-intrinsic protein expression for immunotherapy, using GDSME as prototypic immune modulator. This nanoplatform thus can be applied to modulate further immunological processes for therapeutic benefit.

Biomaterials Facilitating Dendritic Cell‐Mediated Cancer Immunotherapy

“…[ 52 ] Inducing tumor pyroptosis can also release of TAAs to promote cascade‐amplification of the antitumor DC‐immune response. [ 53 ] There have been significant advances in the identification of tumor antigens in recent years. Clinically effective CTL responses have been found to be induced by neoantigens derived from tumor‐specific mutations that accumulate in cancer.…”

Advancing Precision: A Controllable Self-Synergistic Nanoplatform Initiating Pyroptosis-Based Immunogenic Cell Death Cascade for Targeted Tumor Therapy

“…Recently, there has been significant progress in the development of biomaterials designed to load chemotherapy drugs, small molecule drugs, and photosensitizers as pyroptosis inducers to improve tumor immunotherapy. These inducers primarily function by upregulating reactive oxygen species (ROS), causing DNA damage, and disrupting intracellular ion homeostasis as key mechanisms to induce cell pyroptosis. − Among them, ROS, which activates the Cleaved Caspase-3/gasdermin E (GSDME) axis, is considered a powerful candidate for initiating pyroptosis-based ICD owing to its spatiotemporal controllability and advantages of being weakly influenced by tumor heterogeneity. , However, most of the current methods for ROS generation are based on single endogenous (e.g., chemotherapeutic and iron-related treatments) , or exogenous (e.g., photosensitizers) , stimuli, which may be limited by the intrinsic pathological features of malignant cells. , Therefore, synergistic strategies for using different ROS generation mechanisms are urgently needed to overcome the limitations of a single strategy and to amplify ROS with tumor specificity and modulability.…”

Bioorthogonal Disruption of Pyroptosis Checkpoint for High-Efficiency Pyroptosis Cancer Therapy

“…Pyroptosis is an emerging programmed cell death with the characteristics of cell membrane rupture, continuous cell swelling, and leakage of intracellular proinflammatory mediators. − During the pyroptosis process, the formation of inflammasomes activates the caspase 1 and pro-inflammatory cytokines (IL-1β and IL-18), and caspase-1 can cleave gasdermin D to release the N-terminal domain (GSDMD-N) which executes pyroptosis via its pore-forming activity. ,− To date, pyroptosis has attracted widespread concern in cancer therapy, and a variety of nanomaterials have been developed to elicit pyroptosis by photodynamic therapy, chemodynamic therapy, and so on. − However, pyroptosis still inevitably suffers from setbacks arising from the intrinsic adaptive survival mechanism and treatment resistance of cancer cells. ,,,, Notably, recent studies have reported that autophagy may act as a checkpoint to negatively regulate pyroptosis, thus resulting in therapeutic resistance. − …”