Immune checkpoint inhibitors and immunosuppressive tumor microenvironment: current challenges and strategies to overcome resistance.

IF 2.9 4区医学 Q3 IMMUNOLOGY

Immunopharmacology and Immunotoxicology Pub Date : 2025-06-05 DOI:10.1080/08923973.2025.2504906

Gurpreet Singh Gill, Simmi Kharb, Gitanjali Goyal, Prasenjit Das, Kailash Chand Kurdia, Ruby Dhar, Subhradip Karmakar

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引用次数: 0

Abstract

Objectives: Immune checkpoint inhibitors (ICIs) are shown to improve cancer treatment effectiveness by boosting the immune system of the patient. Nevertheless, the unique and highly suppressive TME poses a significant challenge, causing heterogeneity of response or resistance in a considerable number of patients. This review aims to explore the challenges posed by the immunosuppressive tumor microenvironment (TME) in response to immune checkpoint inhibitors (ICIs) and discusses potential strategies to overcome resistance.

Material & methods: A comprehensive review of existing literature was conducted to analyze the immunosuppressive features of the TME, including the role of immunosuppressive cells, cytokine and chemokine signaling, metabolic alterations, and overexpression of immune checkpoint molecules (PD-1, CTLA-4, LAG-3, TIM-3, TIGIT, BTLA). Additionally, strategies to overcome resistance-such as targeting immunosuppressive cells, normalizing tumor vasculature, dual or triple checkpoint blockade, and combining ICIs with vaccines, oncolytic viruses, and metabolic inhibitors-are elaborated. The need for predictive biomarkers to stratify patients and assess treatment response was also discussed.

Results: The review highlights that the immunosuppressive TME contributes significantly to resistance against ICIs, mediated through various mechanisms. Potential strategies to overcome resistance include modulating the TME by targeting immunosuppressive components, combination therapies, and the identification of predictive biomarkers. Further research and innovative approaches are required to fully understand TME-ICI interactions and change the face of cancer treatment.

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免疫检查点抑制剂和免疫抑制肿瘤微环境：当前的挑战和克服耐药性的策略。

免疫检查点抑制剂（ICIs）被证明可以通过增强患者的免疫系统来提高癌症治疗的有效性。然而，独特且高度抑制性的TME带来了重大挑战，在相当多的患者中引起了反应或耐药的异质性。本文主要讨论了TME的回避属性。TME的免疫逃避机制包括免疫抑制细胞、细胞因子和趋化因子信号转导、PD-1、CTLA-4、LAG-3、TIM-3、TIGIT、BTLA等免疫检查点分子的代谢改变和过表达及其在TME内的相互作用。此外，本文综述了通过靶向免疫抑制细胞、使肿瘤血管正常化、同时阻断两个或三个检查点、将疫苗、溶瘤病毒和代谢抑制剂与ICIs或其他疗法联合使用来克服耐药的方法。这篇综述还着重于寻找患者分层的预测标志物和检查ICIs治疗反应的必要性。通过新的研究和智能创新，TME的这些发现及其相互作用如何促进ICI治疗并改变癌症治疗的面貌仍有待确定。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Immunopharmacology and Immunotoxicology 医学-毒理学

CiteScore

5.40

自引率

0.00%

发文量

133

审稿时长

4-8 weeks

期刊介绍： The journal Immunopharmacology and Immunotoxicology is devoted to pre-clinical and clinical drug discovery and development targeting the immune system. Research related to the immunoregulatory effects of various compounds, including small-molecule drugs and biologics, on immunocompetent cells and immune responses, as well as the immunotoxicity exerted by xenobiotics and drugs. Only research that describe the mechanisms of specific compounds (not extracts) is of interest to the journal. The journal will prioritise preclinical and clinical studies on immunotherapy of disorders such as chronic inflammation, allergy, autoimmunity, cancer etc. The effects of small-drugs, vaccines and biologics against central immunological targets as well as cell-based therapy, including dendritic cell therapy, T cell adoptive transfer and stem cell therapy, are topics of particular interest. Publications pointing towards potential new drug targets within the immune system or novel technology for immunopharmacological drug development are also welcome. With an immunoscience focus on drug development, immunotherapy and toxicology, the journal will cover areas such as infection, allergy, inflammation, tumor immunology, degenerative disorders, immunodeficiencies, neurology, atherosclerosis and more. Immunopharmacology and Immunotoxicology will accept original manuscripts, brief communications, commentaries, mini-reviews, reviews, clinical trials and clinical cases, on the condition that the results reported are based on original, clinical, or basic research that has not been published elsewhere in any journal in any language (except in abstract form relating to paper communicated to scientific meetings and symposiums).