Review
. 2026 Sep 15;132(18):e70600.
doi: 10.1002/cncr.70600.
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1 Dana-Farber Cancer Institute, Boston, MA, USA.
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Alissa J Cooper et al.
Cancer.
2026.
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. 2026 Sep 15;132(18):e70600.
doi: 10.1002/cncr.70600.
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1 Dana-Farber Cancer Institute, Boston, MA, USA.
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AbstractPubMedPMID
Abstract
The management of small cell lung cancer (SCLC) has been transformed by the advent of effective T-cell engagers (TCEs), which circumvent the traditionally immunosuppressive tumor microenvironment by directly facilitating T-cell-mediated cell lysis. Delta-like ligand 3 (DLL3) has emerged as the predominant target for TCE development in SCLC given its high expression on tumor cells and relatively spared expression on normal tissues. Tarlatamab, a DLL3xCD3 TCE that is now an approved agent for SCLC, has revolutionized outcomes for patients with SCLC, but raises challenges in terms of toxicity management and real-world implementation. In this review, we discuss the current landscape and future directions of DLL3-targeting TCE in SCLC, including accumulating real-world clinical experience, nascent investigation into patient selection and modifiers of response and resistance, and anticipated paradigm shifts as a result of ongoing clinical trials.
Keywords:
biomarkers; cytokines; immunotherapy; patient selection; small cell lung carcinoma.
© 2026 American Cancer Society. All rights reserved, including rights for text and data mining and training of artificial intelligence technologies or similar technologies.
Conflict of interest statement
A.J.C. has received honoraria from MJH Life Sciences, Ideology Health, Intellisphere LLC, MedStar Health, PeerDirect, PER, and CancerGRACE, and consulting fees from AbbVie, Amgen, AstraZeneca, BI, Daiichi, Gilead Sciences, Novartis, and Regeneron. She reports prior research funding to institution from Merck, Monte Rosa, AbbVie, Roche, Daiichi Sankyo, and Amgen (ended 8/2025). J.S. has received consulting fees from Abbvie, Amgen, Astra Zeneca, Boehringer Ingelheim, Daiichi‐Sankyo, Fosun, Genentech, Gilead, GSK, Jazz Pharmaceuticals, Lilly, Merck, Novartis, Pfizer, Pharma Mar, and Sanofi and research funding from Amgen and Novartis.
Figures
FIGURE 1
(A) Illustration of various T‐cell…
FIGURE 1
(A) Illustration of various T‐cell engager structures and targets. (B) Diagram of mechanism…
FIGURE 1
(A) Illustration of various T‐cell engager structures and targets. (B) Diagram of mechanism of action of cytotoxicity of DLL3‐targeting T‐cell engagers.
FIGURE 2
(A) Pretreatment scans of liver…
FIGURE 2
(A) Pretreatment scans of liver and brain. (B) Scans of liver and brain…
FIGURE 2
(A) Pretreatment scans of liver and brain. (B) Scans of liver and brain 6 weeks after treatment initiation. (C) Pretreatment scans of lung and liver. (D) Scans of lung and liver after three doses of therapy.
References
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MeSH terms
Intracellular Signaling Peptides and Proteins* / antagonists & inhibitors
Intracellular Signaling Peptides and Proteins* / immunology
Intracellular Signaling Peptides and Proteins* / metabolism
Lung Neoplasms* / drug therapy
Lung Neoplasms* / immunology
Lung Neoplasms* / pathology
Membrane Proteins* / antagonists & inhibitors
Membrane Proteins* / metabolism
Small Cell Lung Carcinoma* / drug therapy
Small Cell Lung Carcinoma* / immunology
Small Cell Lung Carcinoma* / pathology
T-Lymphocytes* / drug effects
T-Lymphocytes* / immunology
Tumor Microenvironment / drug effects
Tumor Microenvironment / immunology
Substances
Intracellular Signaling Peptides and Proteins
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