{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T09:22:48Z","timestamp":1783416168895,"version":"3.54.6"},"reference-count":57,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T00:00:00Z","timestamp":1783382400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Small cell lung cancer (SCLC) has historically been treated as a single, uniformly aggressive disease defined by neuroendocrine differentiation, near-universal loss of TP53 and RB1, and the absence of classical druggable oncogene addictions. Two converging lines of evidence are now reshaping that view. First, transcriptomic profiling has resolved SCLC into molecular subtypes\u2014SCLC-A (ASCL1-driven), SCLC-N (NEUROD1-driven), SCLC-P (POU2F3-driven), and SCLC-I (inflamed)\u2014with distinct immune microenvironments, surface-antigen expression patterns, and emerging therapeutic vulnerabilities, although intratumoral heterogeneity and phenotypic plasticity complicate clean subtype assignment. Second, the development of delta-like ligand 3 (DLL3)-directed therapies provides a natural experiment: the same validated surface antigen failed as an antibody\u2013drug conjugate (rovalpituzumab tesirine, three negative randomized trials) yet succeeded as a bispecific T-cell engager (tarlatamab, which received FDA accelerated approval in 2024 and subsequent traditional FDA approval in 2025 following positive confirmatory phase 3 data). In this review, we integrate the current first-line standard of care\u2014chemoimmunotherapy with atezolizumab- or durvalumab-based regimens followed by maintenance intensification with lurbinectedin\u2013atezolizumab (IMforte)\u2014with the molecular framework of subtypes and biomarkers, and we use DLL3 as a case study to propose that delivery modality is an important determinant of therapeutic success in SCLC and should be considered alongside target biology and tumor heterogeneity. Rapid proliferation, antigen heterogeneity, subtype plasticity, and a relatively less immunogenic microenvironment systematically penalize modalities dependent on payload accumulation and cell-cycle progression and reward modalities that recruit catalytic, cell-cycle-independent cytotoxic effectors. The emerging B7-H3 and SEZ6 programs\u2014including ifinatamab deruxtecan and ABBV-706\u2014are the next test of this framework. We discuss implications for biomarker development, trial design, and the operational challenges of subtype-guided precision oncology in a disease where tissue is scarce and biology shifts under therapy.<\/jats:p>","DOI":"10.3390\/cancers18132173","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T08:04:49Z","timestamp":1783411489000},"page":"2173","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Decoding Small Cell Lung Cancer: Molecular Subtypes, Surface Antigens, and the Target-Modality Problem"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-9765-1845","authenticated-orcid":false,"given":"Mijail I.","family":"Zambrano Iglesias","sequence":"first","affiliation":[{"name":"Memorial Cancer Institute, Pembroke Pines, FL 33026, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Rosas","sequence":"additional","affiliation":[{"name":"Memorial Cancer Institute, Pembroke Pines, FL 33026, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salih","family":"Akgun","sequence":"additional","affiliation":[{"name":"Hackensack Meridian Health, JFK University Medical Center, Edison, NJ 08820, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ines C.","family":"Padron Cubillan","sequence":"additional","affiliation":[{"name":"Memorial Cancer Institute, Pembroke Pines, FL 33026, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fedor Wadi","family":"Richani Meinhardt","sequence":"additional","affiliation":[{"name":"Memorial Cancer Institute, Pembroke Pines, FL 33026, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atif","family":"Hussein","sequence":"additional","affiliation":[{"name":"Memorial Cancer Institute, Pembroke Pines, FL 33026, USA"},{"name":"Institute for Human Health and Disease Intervention, Florida Atlantic University (FAU), Jupiter, FL 33458, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2669-5771","authenticated-orcid":false,"given":"Luis E.","family":"Raez","sequence":"additional","affiliation":[{"name":"Memorial Cancer Institute, Pembroke Pines, FL 33026, USA"},{"name":"Institute for Human Health and Disease Intervention, Florida Atlantic University (FAU), Jupiter, FL 33458, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1038\/s41572-020-00235-0","article-title":"Small-cell lung cancer","volume":"7","author":"Rudin","year":"2021","journal-title":"Nat. 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