Beyond success: unveiling the hidden potential of radiotherapy and immunotherapy in solid tumors

Immunotherapy,particularly with immune checkpoint inhibitors,has significantly transformed cancer treatment.Despite its success,many patients struggle to respond adequately or sustain long-lasting clinical improvement.A growing consensus has emerged that radiotherapy(RT)enhances the response rate and overall efficacy of immunotherapy.Although combining RT and immunotherapy has been extensively investigated in preclinical models and has shown promising results,establishing itself as a dynamic and thriving area of research,clinical evidence for this combination strategy over the past five years has shown both positive and disappointing results,suggesting the need for a more nuanced understanding.This review provides a balanced and updated analysis of the combination of immunotherapy and RT.We summarized the preclinical mechanisms through which RT boosts antitumor immune responses andmainly focused on the outcomes of recently updated clinical trials,including those that may not have met expectations.We investigated the optimization of the therapeutic potential of this combined strategy,including key challenges,such as fractionation and scheduling,lymph node irradiation,and toxicity.Finally,we offered insights into the prospects and challenges associated with the clinical translation of this combination therapy,providing a realistic perspective on the current state of research and potential future directions.

Notch signaling pathway:architecture,disease,and therapeutics

The NOTCH gene was identified approximately 110 years ago.Classical studies have revealed that NOTCH signaling is an evolutionarily conserved pathway.NOTCH receptors undergo three cleavages and translocate into the nucleus to regulate the transcription of target genes.NOTCH signaling deeply participates in the development and homeostasis of multiple tissues and organs,the aberration of which results in cancerous and noncancerous diseases.However,recent studies indicate that the outcomes of NOTCH signaling are changeable and highly dependent on context.In terms of cancers,NOTCH signaling can both promote and inhibit tumor development in various types of cancer.The overall performance of NOTCH-targeted therapies in clinical trials has failed to meet expectations.Additionally,NOTCH mutation has been proposed as a predictive biomarker for immune checkpoint blockade therapy in many cancers.Collectively,the NOTCH pathway needs to be integrally assessed with new perspectives to inspire discoveries and applications.In this review,we focus on both classical and the latest findings related to NOTCH signaling to illustrate the history,architecture,regulatory mechanisms,contributions to physiological development,related diseases,and therapeutic applications of the NOTCH pathway.The contributions of NOTCH signaling to the tumor immune microenvironment and cancer immunotherapy are also highlighted.We hope this review will help not only beginners but also experts to systematically and thoroughly understand the NOTCH signaling pathway.