Immunotherapy after EGFR‑TKI treatment in advanced non‑small cell lung cancer - Current status and future perspectives

Sep 23, 2026

Tumor microenvironment (TME) in EGFR‑mutant advanced non‑small cell lung cancer (NSCLC) shows strong immunosuppressive features. EGFR tyrosine kinase inhibitors (EGFR‑TKIs) remodel the TME, promoting immune infiltration of T cells and dendritic cells while reducing suppressive components including tumor‑associated macrophages and regulatory T cells. Continued therapy can shift the TME toward immune escape, with PD‑L1 upregulation and resistance. This creates a transient immunotherapy window where immune checkpoint inhibitors may provide optimal efficacy. The review emphasizes understanding TME dynamics to optimize combination strategies and guide future development.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages17

Reading Time43 min

AccessFree to download

Introduction

Mechanisms of resistance to EGFR‑TKIs

Tumor‑infiltrating immune cells

Immunomodulatory molecules

Immunotherapy clinical trials in EGFR‑mt advanced NSCLC

Discussion and future perspectives

ONCOLOGY REPORTS 55: 44, 2026 Immunotherapy after EGFR‑TKI treatment in advanced non‑small cell lung cancer: Current status and future perspectives (Review) HUIYUAN MA 1,2* , LONGHUI LI2,3* , CONGHAN JIAO 1,2 , YANYAN CHENG 1,2 , JIAYU HE 1,2 , CHEN JIANG 1,2 , QIAN TONG 1,2 , DAN YI2,4 and YING ZHANG 1,2 1 Department of Hematology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P.R. China; 2National Clinical Research Center for Chinese Medicine, Tianjin 300193, P.R. China; 3Department of Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P.R. China; 4 Department of Oncology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin 300193, P.R. China Received June 9, 2025; Accepted January 2, 2026 DOI: 10. 3892/or.2026.9049 Abstract. The tumor microenvironment (TME) of epidermal growth factor receptor (EGFR)‑mutant non‑small cell lung cancer (NSCLC) exhibits notable immunosuppressive properties. EGFR tyrosine kinase inhibitors (EGFR‑TKIs) induce dynamic remodeling of the TME. By boosting the infiltration of immune cells such as T cells and dendritic cells and decreasing immu‑ nosuppressive elements such as tumor‑associated macrophages and regulatory T cells, short‑term TKI treatment can effectively enhance antitumor immunity. However, the TME changes to an immunosuppressive state marked by PD‑L1 upregulation and immune escape with continued therapy and the emergence of resistance. This creates a transient immunotherapy window period during EGFR‑TKI treatment, when immune checkpoint inhibitors may achieve optimal efficacy. It is essential to identify and take advantage of this window in order to enhance treatment results. The present review highlights the importance of under‑ standing TME dynamics in EGFR‑mutant NSCLC to optimize combination strategies and guide future therapeutic development. Contents 1. Introduction 2. Mechanisms of resistance to EGFR‑TKIs Correspondence to: Mrs. Ying Zhang, Department of Hematology, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, 314 Anshanxi Road, Nankai, Tianjin 300193, P.R. China E‑mail: [lll990505@163.com](lll990505@163.com) *Contributed equally Key words: tumor microenvironment, epidermal growth factor receptor‑tyrosine kinase inhibitors, non‑small cell lung cancer, programmed death ligand 1, immune checkpoint inhibitors 3. Tumor‑infiltrating immune cells 4. Immunomodulatory molecules 5. Immunotherapy clinical trials in EGFR‑mt advanced NSCLC 6. Discussion and future perspectives 1. Introduction The major cellular components and mediators of the tumor microenvironment (TME), including cancer cells, immune cells [such as T cells, B cells, dendritic cells (DCs), myeloid‑derived suppressor cells (MDSCs) and tumor‑associated macrophages (TAMs)], stromal cells [cancer‑associated fibroblasts (CAFs) and tumor‑associated endothelial cells], cytokines and chemo‑ kines, tumor vasculature, lymphoid tissue, as well as adipocytesand exosomes, serve a critical role in cancer initiation, progres‑ sion, spread and metastasis (1‑3) . Interactions between the tumor stroma, especially those mediated by CAFs and otherstromal components, actively promote immune evasion and malignant growth in a variety of solid tumors, including lung and breast cancer as well as other epithelial malignancies (2) . Tumor‑infiltrating lymphocytes are a crucial part of antitumor immunity among the immune cells found in tumors and a recent study has demonstrated that immunotherapies can alter TIL activity as well as the interactions between immune and stromal cells in the TME. The TME usually contains signals that inhibit the immune response, such as regulatory T cells (Tregs) and myeloid‑derived suppressor cells, which prevent the infiltration and killing function of immune cells (3) . Breaking through this

FAQs

How do EGFR‑TKIs affect the tumor microenvironment in EGFR‑mutant NSCLC?

Short‑term EGFR‑TKI treatment enhances antitumor immunity by increasing infiltration of immune cells such as T cells and dendritic cells while decreasing immunosuppressive elements including tumor‑associated macrophages and regulatory T cells.

Why does immunotherapy effectiveness change with continued EGFR‑TKI therapy?

With continued therapy, the TME can progress to an immunosuppressive state characterized by PD‑L1 upregulation and immune escape, alongside emergence of resistance.

What is the “transient immunotherapy window” during EGFR‑TKI treatment?

The review describes a period during EGFR‑TKI therapy when TME changes favor immune activation; during this window immune checkpoint inhibitors may achieve optimal efficacy.

Sep 23, 2026

Uploaded by Olivia Brown