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Challenges and Future Perspectives in Treatment for Lung Cancer: 2nd Edition

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 28 February 2027 | Viewed by 13358

Editors

Dr. Ilaria Marrocco

E-Mail Website
Guest Editor
Department of Life Sciences and Public Health, Università Cattolica del Sacro Cuore, 00168 Rome, Italy
Interests: EGFR; lung cancer; tyrosine kinase inhibitors; monoclonal antibodies; drug resistance
Special Issues, Collections and Topics in MDPI journals
Dr. Donatella Romaniello

E-Mail Website
Guest Editor
1. Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Via Massarenti 9, 40138 Bologna, Italy
2. IRCCS Azienda Ospedaliero-Universitaria di Bologna, Via Massarenti 9, 40138 Bologna, Italy
Interests: cancer biology; ErbB family of receptor tyrosine kinases; signal transduction; chemoresistance; immunotherapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Lung cancer, including small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC), is the second most common cancer and the leading cause of cancer-related deaths worldwide. The availability of diverse intervention options (surgery, chemotherapy, radiotherapy, targeted therapy, immunotherapy) has improved the survival of patients in recent decades. However, additional insights must be gained in order to improve the outcome of this disease. 

For this reason, this Special Issue aims to highlight the most recent scientific advances directed at improving the treatment strategies available for both SCLC and NSCLC.

In this Special Issue, original research articles and reviews are welcome. Research areas may include (but are not limited to) the following:

  • Diagnostic, prognostic and predictive biomarkers in lung cancer;
  • Molecular mutations in lung cancer such as the epidermal growth factor receptor (EGFR) gene, ALK rearrangements and KRAS mutations;
  • Epidermal growth factor receptor (EFGR)-targeted therapies and drug resistance;
  • New therapeutic approaches and drug delivery in lung cancer, such as the role of mutation analysis and next-generation sequencing (NGS) in lung cancer diagnosis and treatment.

Research advances in chemotherapy, targeted therapy and immunotherapy are also welcomed.

We look forward to receiving your contributions.

Dr. Ilaria Marrocco
Dr. Donatella Romaniello
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • lung cancer
  • non-small cell lung cancer
  • small cell lung cancer
  • chemotherapy
  • targeted therapy
  • immunotherapy
  • drug resistance
  • drug delivery

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Published Papers (5 papers)

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Research

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25 pages, 22998 KB  
Article
EZH2 Regulates the Proliferation-Senescence Balance and Tumor–Stromal Signaling in Lung Adenocarcinoma
by Kamil Saramowicz, Matylda Piesiewicz, Angelika A. Adamus-Grabicka, Pengyu Zhao, Joanna Sikora and Wioletta Rozpędek-Kamińska
Int. J. Mol. Sci. 2026, 27(13), 5914; https://doi.org/10.3390/ijms27135914 - 30 Jun 2026
Viewed by 552
Abstract
Enhancer of zeste homolog 2 (EZH2), the catalytic component of the polycomb repressive complex 2, is frequently overexpressed in lung adenocarcinoma and contributes to transcriptional programs that support tumor proliferation and cellular plasticity. However, its role in regulating senescence-associated signaling and tumor–stromal interactions [...] Read more.
Enhancer of zeste homolog 2 (EZH2), the catalytic component of the polycomb repressive complex 2, is frequently overexpressed in lung adenocarcinoma and contributes to transcriptional programs that support tumor proliferation and cellular plasticity. However, its role in regulating senescence-associated signaling and tumor–stromal interactions in lung cancer remains incompletely understood. In this study, we combined transcriptomic analysis of The Cancer Genome Atlas lung adenocarcinoma cohort with functional characterization of EZH2 targeting in A549 cells using the catalytic inhibitor EPZ6438 and the EZH2 degrader MS1943. Elevated EZH2 expression was associated with enrichment of cell cycle-related transcriptional pathways. Pharmacological targeting of EZH2 reduced proliferation, migration, stemness-associated features, and sphere-forming capacity, with more pronounced effects observed following EZH2 degradation. Both compounds promoted features consistent with senescence-associated phenotypic remodeling characterized by increased expression of p16 and p21, enhanced β-galactosidase activity, G0/G1 cell cycle arrest, and increased expression of cytokines commonly associated with senescence-related secretory signaling, including IL-6, CCL2, and CXCL8. Conditioned medium from treated tumor cells promoted activation of primary lung fibroblasts, indicating functional paracrine microenvironmental remodeling. Importantly, EZH2 targeting elicited cytostatic responses without induction of apoptosis. Collectively, these findings suggest that EZH2 contributes to regulation of proliferation-associated and senescence-associated phenotypic programs together with stromal signaling in lung adenocarcinoma. Full article
(This article belongs to the Special Issue Challenges and Future Perspectives in Treatment for Lung Cancer: 2nd Edition)
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17 pages, 8635 KB  
Article
Carcinoembryonic Antigen-Related Cell Adhesion Molecule 5 as a Biomarker for Predicting Response to Erlotinib and Gefitinib in Lung Adenocarcinoma: An Integrative Analysis of Transcriptomic Data of PC-9 and Drug-Resistant PC-9 Cell Lines
by Pritsana Raungrut, Suchanan Tanyapattrapong, Saowanee Maungchanburi and Kanyaphak Bumrungchoo
Int. J. Mol. Sci. 2026, 27(7), 3092; https://doi.org/10.3390/ijms27073092 - 28 Mar 2026
Viewed by 838
Abstract
Erlotinib (ER) and gefitinib (GB) are frequently prescribed for patients with advanced lung adenocarcinoma (ADC). Although both ER and GB significantly extend median survival, several patients experience early disease relapse due to treatment resistance. This study aimed to identify common genes associated with [...] Read more.
Erlotinib (ER) and gefitinib (GB) are frequently prescribed for patients with advanced lung adenocarcinoma (ADC). Although both ER and GB significantly extend median survival, several patients experience early disease relapse due to treatment resistance. This study aimed to identify common genes associated with acquired resistance to ER or GB. This integrative analysis of transcriptomic data identified differentially expressed genes by comparing sensitive PC-9 cells with ER-resistant (PC-9/ER) or GB-resistant (PC-9/GB) cell lines. A Venn diagram was used to identify common genes. Candidate genes were confirmed in our generated drug-resistant cell lines. After six months, the PC-9/ER and PC-9/GB cell lines exhibited 40.7-fold and 109.2-fold increases in resistance to ER and GB, respectively. Flow cytometric analysis demonstrated that both resistant cell lines were resistant to cell cycle arrest and apoptosis induced by ER or GB. Through integrated analysis, we found that two genes, KRT13 and CEACAM5, were up-regulated in both the PC-9/ER and PC-9/GB cell lines. The expression patterns of these two genes did not align with the transcriptome, with only CEACAM5 exhibiting consistent gene and protein expressions. Our findings indicate that CEACAM5 serves as a biomarker for predicting the response of patients to ER and GB treatments. Full article
(This article belongs to the Special Issue Challenges and Future Perspectives in Treatment for Lung Cancer: 2nd Edition)
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Review

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35 pages, 13733 KB  
Review
Endobronchial Intratumoral Immuno- and Gene Therapies in Lung Cancer: Mechanisms of Local Delivery, Systemic Immune Effects, and Global Feasibility
by Mihai Olteanu, Gabriela Marina Andrei, Ramona Cioboată and Virginia Maria Rădulescu
Int. J. Mol. Sci. 2026, 27(15), 6988; https://doi.org/10.3390/ijms27156988 - 4 Aug 2026
Viewed by 503
Abstract
Lung cancer remains the leading cause of cancer-related mortality worldwide, and durable benefit from immune checkpoint inhibitors is limited by immune exclusion, microenvironmental immunosuppression, and toxicity. This narrative translational review evaluates whether endobronchial intratumoral delivery of immuno- and gene-based therapies can transform bronchoscopic [...] Read more.
Lung cancer remains the leading cause of cancer-related mortality worldwide, and durable benefit from immune checkpoint inhibitors is limited by immune exclusion, microenvironmental immunosuppression, and toxicity. This narrative translational review evaluates whether endobronchial intratumoral delivery of immuno- and gene-based therapies can transform bronchoscopic access into a therapeutic platform linking local tumour intervention with systemic antitumour immunity. We synthesise evidence on endobronchial ultrasound, electromagnetic navigation bronchoscopy, and robotic-assisted bronchoscopy, together with local checkpoint blockade, cytokine and mRNA-lipid nanoparticle constructs, oncolytic virotherapy, dendritic-cell approaches, viral and non-viral gene transfer, and enzyme- or metabolite-based strategies. Current clinical evidence remains preliminary, consisting mainly of Phase I trials, small prospective cohorts, and case-based signals, with feasibility and safety observations but no completed randomised trial demonstrating efficacy against standard-of-care systemic therapy. The most plausible candidates are patients with advanced or recurrent NSCLC, bronchoscopically accessible lesions, inadequate response to systemic immunotherapy, and immune-excluded or locally immunosuppressed tumours. Biomarkers such as PD-L1, tumour mutational burden, CD8+ infiltration, tertiary lymphoid structures, radiomics, and circulating tumour DNA require validation. This review integrates delivery technology, immune mechanisms, statistical evidence appraisal, biomarker limitations, AI-guided planning, and global feasibility. Full article
(This article belongs to the Special Issue Challenges and Future Perspectives in Treatment for Lung Cancer: 2nd Edition)
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28 pages, 1018 KB  
Review
Tyrosine Kinase Inhibitors, Antibody–Drug Conjugates, and Bispecific Antibodies in Oncogene-Driven Non-Small-Cell Lung Cancer: Evolving Roles in Treatment Sequencing and Resistance Management
by Saba Musleh Ud Din, Amy Kiamos, Sundas Ali, Meri Muminovic Mehta and Luis E. Raez
Int. J. Mol. Sci. 2026, 27(14), 6251; https://doi.org/10.3390/ijms27146251 - 14 Jul 2026
Viewed by 704
Abstract
The treatment landscape of oncogene-driven non-small-cell lung cancer (NSCLC) has evolved substantially with the development of targeted therapies directed against actionable molecular alterations. Tyrosine kinase inhibitors (TKIs) remain the cornerstone of treatment for many driver-defined subsets; however, acquired resistance, central nervous system progression, [...] Read more.
The treatment landscape of oncogene-driven non-small-cell lung cancer (NSCLC) has evolved substantially with the development of targeted therapies directed against actionable molecular alterations. Tyrosine kinase inhibitors (TKIs) remain the cornerstone of treatment for many driver-defined subsets; however, acquired resistance, central nervous system progression, and tumor heterogeneity continue to limit long-term disease control. This review examines the mechanistic foundations, clinical evidence, resistance patterns, and emerging therapeutic roles of TKIs, antibody–drug conjugates (ADCs), and bispecific antibodies (bsAbs) in oncogene-driven NSCLC. Relevant preclinical studies, clinical trials, and recent therapeutic advances across major actionable driver alterations were reviewed and compared. TKIs provide potent and selective inhibition of oncogenic signaling and remain the preferred frontline therapy in most molecular subgroups, whereas ADCs offer targeted payload delivery that may overcome diverse resistance mechanisms, and bsAbs provide dual-target blockade and immune-mediated antitumor activity. Emerging evidence supports the expanding role of ADCs and bsAbs in post-TKI settings and selected biomarker-defined populations. Resistance mechanisms differ across therapeutic classes and include secondary target alterations, bypass pathway activation, antigen loss, payload resistance, and receptor adaptation. Collectively, these modalities are increasingly being integrated into biomarker-guided treatment strategies, with future management likely to rely on rational sequencing and combination approaches tailored to resistance mechanisms, target expression, central nervous system involvement, and tumor heterogeneity. Full article
(This article belongs to the Special Issue Challenges and Future Perspectives in Treatment for Lung Cancer: 2nd Edition)
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36 pages, 1951 KB  
Review
Advances in Targeted Therapy for Non-Small-Cell Lung Cancer: Current Progress and Future Directions
by Supriya Peshin, Ehab Takrori, Joseph H. Yazji, Johum Haque, Adit Dharia, Mohammad Sajid Mithani, Fnu Anum, Ummul Asfeen, Jill Kristen Couch, Mabe Donovan and Sakshi Singal
Int. J. Mol. Sci. 2025, 26(23), 11517; https://doi.org/10.3390/ijms262311517 - 27 Nov 2025
Cited by 10 | Viewed by 10208
Abstract
The advent of targeted therapies has significantly transformed the management of non-small-cell lung cancer (NSCLC), improving survival across all disease stages. Discoveries of both common and rare oncogenic drivers are advancing rapidly, posing a challenge for clinicians and researchers to remain up to [...] Read more.
The advent of targeted therapies has significantly transformed the management of non-small-cell lung cancer (NSCLC), improving survival across all disease stages. Discoveries of both common and rare oncogenic drivers are advancing rapidly, posing a challenge for clinicians and researchers to remain up to date in this dynamic field. This review highlights the evolving landscape of therapeutic strategies for actionable mutations in lung cancer, with particular attention given to the latest developments in KRAS-targeted treatments including non-G12C mutations, pan-RAS inhibitors, and agents targeting RAS-GTP. We also examine the existing standards of care for NSCLC harboring EGFR and ALK alterations, as well as emerging therapies poised for clinical use. Additional discussion includes advancements in therapies directed at MET, HER2, RET, ROS1, and FGFR alterations—each representing promising targets in NSCLC. This review concludes by exploring the growing evidence surrounding TROP-2 as a novel therapeutic target, especially relevant in cases where previous targeted treatments have failed. Full article
(This article belongs to the Special Issue Challenges and Future Perspectives in Treatment for Lung Cancer: 2nd Edition)
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