Brain metastases and lung cancer - molecular biology, natural history, prediction of response and efﬁcacy of immunotherapy

Sep 21, 2026

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Brain metastases arising from lung cancer are a frequent, difficult complication that strongly affects patients’ overall health. The review explains how molecular alterations and a supportive CNS environment enable cancer-cell migration from lung lesions to neural tissue. It evaluates how immunotherapy and its combinations in non-small cell lung cancer improve survival and show better central nervous system penetration than traditional chemotherapy. It summarizes mechanisms of brain metastasis development and assesses efficacy of novel immunotherapy strategies and combinations.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages13

Reading Time33 min

AccessFree to download

1 Introduction

1.1 Epidemiology and risk factors

2 Brain organotropism in lung cancer

TYPE Review PUBLISHED 12 January 2024 DOI 10.3389/fimmu.2023.1297988 OPEN ACCESS EDITED BY Laura Senovilla, Spanish National Research Council (CSIC), Spain REVIEWED BY Raees Tonse, Baptist Hospital of Miami, United States Stefania Canova, San Gerardo Hospital, Italy *CORRESPONDENCE Maria Sereno [mariasereno75@gmail.com](mariasereno75@gmail.com) RECEIVED 28 September 2023 ACCEPTED 18 December 2023 PUBLISHED 12 January 2024 CITATION Sereno M, Hernandez de Co´rdoba I, Gutie´ rrez-Gutie´ rrez G and Casado E (2024) Brain metastases and lung cancer: molecular biology, natural history, prediction of response and efﬁcacy of immunotherapy. Front. Immunol. 14:1297988 . doi: 10.3389/fimmu.2023.1297988 COPYRIGHT © 2024 Sereno, Hernandez de Co´rdoba, Gutie´ rrez-Gutie´rrez and Casado. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. Brain metastases and lung cancer: molecular biology, natural history, prediction of response and efﬁcacy of immunotherapy Maria Sereno 1,2,3,4*, Irene Hernandez de Co´ rdoba 1, Gerardo Guti´errez-Guti´errez 2,3,5 and Enrique Casado 1,2,3,4 1 Medical Oncology Department, Infanta Sofía University Hospital, Madrid, Spain, 2 European University of Madrid, Madrid, Spain, 3 Fundación para la Innovación e Investigación Biomédica (FIIB) Hospital Universitario Infanta Sofía (HUIS) Hospital de Henares (HHEN), Madrid, Spain, 4 Instituto Madrileño Investigación Estudios Avanzados (IMDEA), Precision Nutrition and Cancer Program, Clinical Oncology Group, IMDEA Food Institute, CEI Universidad Autónoma de Madrid (UAM), Consejo Superior de Investigaciones Cientíﬁcas (CSIC), Madrid, Spain, 5 Neurology Department, Infanta Sofía University Hospital, Madrid, Spain Brain metastases stemming from lung cancer represent a common and challenging complication that signiﬁcantly impacts patients ’ overall health. The migration of these cancerous cells from lung lesions to the central nervous system is facilitated by diverse molecular changes and a speciﬁc environment that supports their afﬁnity for neural tissues. The advent of immunotherapy and its varied combinations in non-small cell lung cancer has notably improved patient survival rates, even in cases involving brain metastases. These therapies exhibit enhanced penetration into the central nervous system compared to traditional chemotherapy. This review outlines the molecular mechanisms underlying the development of brain metastases in lung cancer and explores the efﬁcacy of novel immunotherapy approaches and their combinations KEYWORDS brain metastasis, organotropism, immunotherapy, abscopal effect, intracranial activity 1 Introduction Lung cancer (LC) stands as the leading cause of cancer-related deaths, with brain involvement accounting for a signiﬁcant portion of this mortality rate. LC contributes to approximately 50% of all brain metastases (BM) cases following melanoma (1, 2) . The incidence of this complication is notably prominent in tumors featuring activating mutations (EGFR, ALK, and ROS-1) . However, in patients without these molecular alterations, the incidence of brain involvement varies, occurring both at diagnosis and at different stages during the progression of their disease (3) . The development of targeted Frontiers in Immunology 01 [frontiersin.org](frontiersin.org) therapies and immunotherapy has substantially enhanced the prognosis of non-small cell lung cancer (NSCLC) with brain metastases. This progress is particularly signiﬁcant for patients with molecular alterations due to the emergence of increasingl

FAQs

What enables lung cancer to spread to the brain?

Brain metastases develop through molecular changes and a CNS environment that support neural tissue affinity, along with processes such as blood-brain barrier disruption and tumor microenvironment interactions.

How does immunotherapy change outcomes for patients with brain metastases?

Immunotherapy combinations improve survival in non-small cell lung cancer, with enhanced penetration into the central nervous system compared with traditional chemotherapy.

What risk factors are associated with developing brain metastases?

Reported risk factors include age ≤ 60 years, non-squamous histology, and bulky mediastinal lymph nodes (>2 cm), along with classic prognostic factors such as KPS > 70% and absence of extracranial metastases.

Sep 21, 2026

Uploaded by Logic