The role of macrophages in non-small cell lung cancer and advancements in 3D cocultures - Review Article

Sep 24, 2026

Lung cancer remains the leading cause of cancer-related death worldwide, and conventional chemotherapy or radiotherapy yields only limited benefit. Targeted inhibitors for common non-small cell lung cancer (NSCLC) genetic aberrations improve outcomes, yet only a subset of patients responds due to the complexity of the mutational landscape and development of resistance. Attention has shifted toward tumor-promoting inflammation driven by the immune infiltrate, particularly macrophages, whose plasticity influences early establishment, malignant progression, and invasion. Emerging strategies aim to re-differentiate macrophages, deplete pro-tumor subsets, or combine them with cytotoxic or immunotherapeutic agents using advanced 3D co-culture and organoid models.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages21

Reading Time53 min

AccessFree to download

Introduction

Non-small cell lung cancer overview and treatment limits

Tumor microenvironment and immune involvement

Macrophage roles and therapeutic directions

Plasticity, tumor-promoting phenotypes, and invasion

Emerging macrophage-targeting therapies

Advancements in 3D co-culture models

Need for complex models beyond 2D and murine systems

Organoids and immune-epithelial interaction modeling

RevIeW ARtICLe *For correspondence: [a.dost@hubrecht.eu](a.dost@hubrecht.eu)[ ](a.dost@hubrecht.eu)Competing interest: See page 14 Funding: See page 14 Received: 02 November 2022 Accepted: 09 February 2023 Published: 21 February 2023 The role of macrophages in non-small cell lung cancer and advancements in 3D cocultures Katarína Balážová1,2, Hans Clevers3, Antonella FM Dost1,2* 1 Hubrecht Institute for Developmental Biology and Stem Cell Research-KNAW & University Medical Centre Utrecht, Utrecht, Netherlands; 2Oncode Institute, Hubrecht Institute-KNAW, Utrecht, Netherlands; 3 Roche Pharma Research and early Development, Basel, Switzerland Abstract Lung cancer (LC) is the leading cause of cancer-related deaths worldwide. Traditional therapeutic approaches such as chemotherapy or radiotherapy have provided only a marginal improvement in the treatment of lung carcinomas. Inhibitors targeting specific genetic aberrations present in non-small cell lung cancer (NSCLC), the most common subtype (85%), have improved the prognostic outlook, but due to the complexity of the LC mutational spectrum, only a fraction of patients benefit from these targeted molecular therapies. More recently, the realization that the immune infiltrate surrounding solid tumors can foster tumor-promoting inflammation has led to the development and implementation of anticancer immunotherapies in the clinic. In NSCLC, one of the most abundant leukocyte infiltrates is macrophages. These highly plastic phagocytes, which are part of the cellular repertoire of the innate immunity, can have a pivotal role in early NSCLC establishment, malignant progression, and tumor invasion. Emerging macrophage-targeting therapies have been focused on the re-differentiation of the macrophages toward an antitumorigenic phenotype, depletion of tumor-promoting macrophage subtypes, or combination therapies combining traditional cytotoxic treatments with immunotherapeutic agents. The most extensively used models employed for the exploration of NSCLC biology and therapy have been 2D cell lines and murine models. However, studying cancer immunology requires appropriately complex models. 3D platforms, including organoid models, are quickly advancing powerful tools to study immune cell-epithelial cell interactions within the tumor microenvironment. Co-cultures of immune cells along with NSCLC organoids allow for an in vitro observation of the tumor microenvironment dynamics closely resembling in vivo settings. Ultimately, the implementation of 3D organoid technology into tumor microenvironment-modeling platforms might facilitate the exploration of macrophagetargeted therapies in NSCLC immunotherapeutic research, thus establishing a new frontier in NSCLC treatment. Reviewing Editor: Xiaoyu Hu, Tsinghua University, China Copyright Balážová et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use andredistribution provided that the original author and source are credited. Introduction Lung cancer (LC) is the leading cause of cancer-associated death worldwide with an average survival being less than 5 years’ post-diagnosis (Ferlay et al., 2021) . Mortality due to LC surpasses the combined mortalities caused by breast, colon, and prostate malignancies (Howlader, 2020) . The two primary histological LC types are small cell lung cancer (SCLC), encompassing about 15% of all cases, and non-small cell lung cancer (NSCLC), the predominant subtype accounting for about 85% of cases (Conway et al., 2016; Li et al., 2020) . Further sub-division of NSCLC includes lung adenocarcinoma (LUAD, ~40%), lung squamous cell carcinoma (LUSC, ~25%), and large cell carcinoma (~10%)(Arora et al., 2021) . While surgical tumor resection has the greatest success therapeutically, the vast Balážová et al. eLife 2023;12:e82998. DOI: [https://doi.org/10.7554/eLife.82998](https://doi.org/10.7554/eLife.82998) 1 of 21 Review

FAQs

Why do targeted therapies for NSCLC benefit only some patients?

Targeted inhibitors improve response rates, but their utility is limited because the NSCLC mutational landscape is complex. Tumors also often acquire resistance, further reducing long-term survival gains.

What role do macrophages play in NSCLC?

Macrophages are abundant immune infiltrates in NSCLC and are highly plastic innate immune phagocytes. They can influence early tumor establishment, malignant progression, and tumor invasion.

How do 3D coculture and organoid models improve NSCLC immunology studies?

Studying cancer immunology requires appropriately complex models. Co-culturing immune cells with NSCLC organoids enables in vitro observation of tumor microenvironment dynamics that more closely resemble in vivo conditions.

Sep 24, 2026

Uploaded by CatatanPagi