Metabolic regulation of innate immunity in cancer immunotherapy

Innate immunity,originally recognized as the primary defense mechanism against pathogenic infections,has also been shown to have an important role in anti-tumor immunity.Host cells recognize cytosolic DNA and RNA,which triggers a cascade of signaling events via nucleic-acid sensing receptors,including endosomal Toll-like receptors(TLRs),cytoplasmic cyclic GMP-AMP synthase(cGAS)for double-stranded DNA sensing,and cytoplasmic retinoic acid-inducible gene I(RIG-I)for double-stranded RNA detection.

Triplex-structure based DNA circuits with ultra-low leakage and high signal-to-noise ratio

DNA circuits are powerful tools in various applications such as logical computation,molecular diagnosis and synthetic biology.Leakage is a major problem in constructing complex DNA circuits.It directly affects the output signal and harms the circuit’s performance significantly.In the traditional DNA circuits,the gate complex is a duplex structure.There are insufficient energy barriers to prevent spontaneous detachment of strands,resulting in a leak prone.Herein,we have developed triplex-structure based DNA circuit with ultra-low leakage and high signal-to-noise ratio(SNR).The triplex structure improves the stability in the absence of input.At the same time,the driving force of the strand displacement cascades reduces the influence of the triplex structure on the desired reaction.The SNR of the DNA circuit was increased to 695,while the desired reaction rate remained 90%of the conventional translator circuit.The triplex-structure mediated leakage prevention strategy was further tested at different temperatures and in DNA translator and seesaw circuits.We also constructed modular basic logic gates with a high efficiency and low leakage.On this basis,we further constructed triplex-structure based tertiary DNA logic circuits,and the SNR reached 295,which,to the best of our knowledge,was among the highest of the field.We believe that our scheme provides a novel,valid,and general tool for reducing leakages,and we anticipate that it will be widely adopted in DNA nanotechnology.

Harnessing innate immune pathways for therapeutic advancement in cancer

The innate immune pathway is receiving increasing attention in cancer therapy.This pathway is ubiquitous across various cell types,not only in innate immune cells but also in adaptive immune cells,tumor cells,and stromal cells.Agonists targeting the innate immune pathway have shown profound changes in the tumor microenvironment(TME)and improved tumor prognosis in preclinical studies.However,to date,the clinical success of drugs targeting the innate immune pathway remains limited.Interestingly,recent studies have shown that activation of the innate immune pathway can paradoxically promote tumor progression.The uncertainty surrounding the therapeutic effectiveness of targeted drugs for the innate immune pathway is a critical issue that needs immediate investigation.In this review,we observe that the role of the innate immune pathway demonstrates heterogeneity,linked to the tumor development stage,pathway status,and specific cell types.We propose that within the TME,the innate immune pathway exhibits multidimensional diversity.This diversity is fundamentally rooted in cellular heterogeneity and is manifested as a variety of signaling networks.The pro-tumor effect of innate immune pathway activation essentially reflects the suppression of classical pathways and the activation of potential pro-tumor alternative pathways.Refining our understanding of the tumor's innate immune pathway network and employing appropriate targeting strategies can enhance our ability to harness the anti-tumor potential of the innate immune pathway and ultimately bridge the gap from preclinical to clinicalapplication.