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Background and Aims: Major genomic drivers of hepatocellular carcinoma (HCC) are nowadays well recognized, although models to establish their roles in human HCC initiation remain scarce. Here, we used human liver organoids in experimental systems to mimic the early stages of human liver carcinogenesis from the genetic lesions of TP53 loss and L3 loop R249S mutation. In addition, chromatin immunoprecipitation sequencing (ChIP‐seq) of HCC cell lines shed important functional insights into the initiation of HCC consequential to the loss of tumor‐suppressive function from TP53 deficiency and gain‐of‐function activities from mutant p53. Approach and Results: Human liver organoids were generated from surgical nontumor liver tissues. CRISPR knockout of TP53 in liver organoids consistently demonstrated tumor‐like morphological changes, increased in stemness and unrestricted in vitro propagation. To recapitulate TP53 status in human HCC, we overexpressed mutant R249S in TP53 knockout organoids. A spontaneous increase in tumorigenic potentials and bona fide HCC histology in xenotransplantations were observed. ChIP‐seq analysis of HCC cell lines underscored gain‐of‐function properties from L3 loop p53 mutants in chromatin remodeling and overcoming extrinsic stress. More importantly, direct transcriptional activation of PSMF1 by mutant R249S could increase organoid resistance to endoplasmic reticulum stress, which was readily abrogated by PSMF1 knockdown in rescue experiments. In a patient cohort of primary HCC tumors and genome‐edited liver organoids, quantitative polymerase chain reaction corroborated ChIP‐seq findings and verified preferential genes modulated by L3 mutants, especially those enriched by R249S. Conclusions: We showed differential tumorigenic effects from TP53 loss and L3 mutations, which together confer normal hepatocytes with early clonal advantages and prosurvival functions.

Despite recent progress in treating advanced non-small cell lung cancer, clinical intervention in extensive-stage small-cell lung cancer (ES-SCLC) remains stagnant. The purpose of this study was to evaluate the clinical efficacy of cytokine-induced killer (CIK) cells combined with cytotoxic chemotherapy, followed by anti-programmed death 1 antibody (sintilimab) maintenance, in ES-SCLC patients. To explore a new method for safe treatment of ES-SCLC patients, thirteen ES-SCLC patients were enrolled between June 2019 and December 2021. All patients received first-line chemotherapy (etoposide plus platinum) combined with CIK cell therapy. Patients who reached a stable disease state or responded well to treatment received sintilimab maintenance treatment. The primary objective of this study was to determine the median overall survival (OS); the secondary objective was to assess the objective response rate (ORR), progression-free survival 1 and 2 (PFS1 was defined as the duration from the signing of informed consent to the date of tumor progression, or death, or the last follow-up. PFS2 was defined as the duration from the first day of sintilimab treatment to the date of tumor progression, death, or the last follow-up.), and adverse reactions. At a 24.1-month follow-up, the median OS was 11.8 (95% confidence interval [CI]: 10.6–13.0) months, median PFS1 was 5.5 (95% CI: 5.0–6.0) months, and the median PFS2 was 2.3 (95% CI: 0.5–4.1) months. The ORR was 76.9% (10/13), the disease control rate was 100% (13/13), and the 20-month survival rate was 41.7%. Eight participants exhibited grade 3 or 4 adverse events after combination therapy. During maintenance treatment with sintilimab, level 3 adverse events occurred in 1 patient (1/9). In conclusion, adding CIK cells to standard chemotherapy regimens, followed by maintenance therapy with sintilimab, may represent a new safe and effective treatment strategy.Clinical trial registrationClinicalTrials.gov (NCT03983759)