免疫检查点抑制剂（ICIs）是一类不断扩大的免疫治疗药物，有潜力治愈癌症。尽管患者亚群的临床反应卓越，但大多数人会变得难治性或产生耐药性。缺乏预测性反应标志物限制了患者分层和个体化免疫治疗。最近的研究发现，主导免疫细胞组成、T细胞状态和异质性，以及免疫细胞在肿瘤微环境（TME）内的时空分布模式正在成为预后和治疗反应的重要决定因素。在这个背景下，ICIs也作为实验工具和概念验证的手段，验证了所鉴定机制的可行性。本文在审视ICIs当前状态后，将探讨基于最新发现的新的综合预测标志物。我们将讨论将TME分类为免疫原型的建立，作为个体化免疫分析的工具，允许在ICIs治疗之前对患者进行分层。我们将讨论对T细胞多样性的逐渐理解及其在塑造患者免疫特征中的作用。我们描述了评分T细胞与TME的其他细胞组分之间相互时空调节的潜力策略。此外，我们还将概述一系列合成和天然或衍生小分子。我们将比较最近通过基于计算机预测识别的化合物与湿实验验证的候选药物，它们有潜力作为ICIs和/或调节TME的细胞组分的调节剂。版权所有 © 2023 作者. 由 Elsevier Ltd. 发布。保留所有权利。

Immune checkpoint inhibitors (ICIs) are an expanding class of immunotherapeutic agents with the potential to cure cancer. Despite the outstanding clinical response in patient subsets, most individuals become refractory or develop resistance. Patient stratification and personalized immunotherapies are limited by the absence of predictive response markers. Recent findings show that dominant patterns of immune cell composition, T-cell status and heterogeneity, and spatiotemporal distribution of immune cells within the tumor microenvironment (TME) are becoming essential determinants of prognosis and therapeutic response. In this context, ICIs also function as investigational tools and proof of concept, allowing the validation of the identified mechanisms. After reviewing the current state of ICIs, this article will explore new comprehensive predictive markers for ICIs based on recent discoveries. We will discuss the recent establishment of a classification of TMEs into immune archetypes as a tool for personalized immune profiling, allowing patient stratification before ICI treatment. We will discuss the developing comprehension of T-cell diversity and its role in shaping the immune profile of patients. We describe the potential of strategies that score the mutual spatiotemporal modulation between T-cells and other cellular components of the TME. Additionally, we will provide an overview of a range of synthetic and naturally occurring or derived small molecules. We will compare compounds that were recently identified by in silico prediction to wet lab-validated drug candidates with the potential to function as ICIs and/or modulators of the cellular components of the TME.Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.