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Small-cell lung cancer (SCLC) is speculated to harbor complex genomic intratumor heterogeneity (ITH) associated with high recurrence rate and suboptimal response to immunotherapy. Here, we revealed a rather homogeneous mutational landscape but extremely suppressed and heterogeneous T cell receptor (TCR) repertoire in SCLCs. Higher mutational burden, lower chromosomal copy number aberration (CNA) burden, less CNA ITH and less TCR ITH were associated with longer overall survival of SCLC patients. Compared to non-small cell lung cancers (NSCLCs), SCLCs had similar predicted neoantigen burden and mutational ITH, but significantly more suppressed and heterogeneous TCR repertoire that may be associated with higher CNA burden and CNA ITH in SCLC. Novel therapeutic strategies targeting CNA could potentially improve the tumor immune microenvironment and response to immunotherapy in SCLC. ### Competing Interest Statement L.A.B. serves on advisory committees for AstraZeneca, AbbVie, GenMab, BergenBio, Pharma Mar SA, Sierra Oncology, Merck, Bristol Myers Squibb, Genentech, and Pfizer and has research support from AbbVie, AstraZeneca, GenMab, Sierra Oncology and Tolero Pharmaceuticals. I.W reports grants and personal fees from Genentech/Roche, grants and personal fees from Bayer, grants and personal fees from Bristol-Myers Squibb, grants and personal fees from AstraZeneca/Medimmune, grants and personal fees from Pfizer, grants and personal fees from HTG Molecular, grants and personal fees from Merck, personal fees from GlaxoSmithKline, grants and personal fees from Guardant Health, personal fees from MSD, grants from Oncoplex, grants from DepArray, grants from Adaptive, grants from Adaptimmune, grants from EMD Serono, grants from Takeda, grants from Amgen, grants from Karus, grants from Johnson & Johnson, grants from Iovance, grants from 4D, grants from Novartis, grants from Oncocyte, grants from Akoya. J.Z reports research funding and personal fees from BMS, Johnson and Johnson, AstraZeneca, Geneplus, OrigMed, Innovent and Merck, outside the submitted work. The remaining authors declare no competing interests.

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