Trastuzumab deruxtecan (T-DXd) is a transformative HER2-targeting antibody–drug conjugate (ADC) for treating breast cancer. Unfortunately, T-DXd has also been implicated in causing fatal interstitial lung disease (ILD) in multiple clinical trials. A better understanding of the mechanistic basis of these ADC-induced adverse effects could enable development of strategies to prevent or treat T-DXd–related ILD. In this study, we determined that T-DXd–induced ILD represents an off-target adverse event rather than an on-target off-tumor adverse event. To further investigate this phenomenon, an immunocompetent murine model that recapitulates T-DXd–induced ILD events was developed, facilitating in-depth mechanistic studies. Single-cell RNA sequencing in this model implicated alveolar macrophages (AM) as the primary cell type impacted by T-DXd in the lung microenvironment. Intravital microscopy further revealed that AMs resident in perivascular niches directly engulfed blood-circulating T-DXd via Fc–FcγR engagement. This Fc–FcγR interaction with T-DXd triggered a phenotypic shift in AMs from an immunosuppressive to a pro-ILD state, characterized by inflammation and immune activation, mediated through the SPP1 pathways. Finally, mitigating nonspecific T-DXd uptake in the lung by preconditioning perivascular AMs with IgG1 or the parental antibody of T-DXd significantly reduced unintended ADC absorption. These findings elucidate a mechanism by which T-DXd ignites the lung immune microenvironment and underscore the importance of off-target endocytosis by innate immune cells in the development of ADC-related toxicities. Significance: Preconditioning the perivascular niche can prevent lung inflammation induced by antibody-drug conjugate phagocytosis by alveolar macrophages and subsequent SPP1high macrophage differentiation, providing a clinically viable strategy for mitigating interstitial lung disease.

Purpose. Immunotherapy provides a new treatment option for advanced gastric cancer (AGC). This study aims to explore the response markers of immunotherapy in AGCs. Methods. Next-generation sequencing was performed on 44 AGC patients who received immune checkpoint inhibitors and the associations between their outcomes after combination immunotherapy, and the clinicopathological/molecular characteristics were analyzed. Results. The current study cohort had a median progression-free survival (PFS) of 5.9 months, an overall survival (OS) of 12.1 months, and an objective response rate (ORR) of 36.4%. Through multivariable analysis of the clinical characteristics, primary tumor resection (HR = 2.66, 95% CI: 1.06–6.70, ) and increased proportion of lymphocytes after combination immunotherapy (HR = 0.40, 95% CI: 0.16–0.99, ) were revealed as independent predictors for patient outcomes. All the 18 patients who underwent genetic profiling were microsatellite-stable with a median TMB of four mutations per Mb. ATM alterations, PI3K pathway mutations, increased TMB, and positive PD-L1 expression were associated with the increased trend of PFS and ORR. According to the combination of baseline lymphocyte count, ATM mutation, TMB status, and PD-L1 expression, patients were stratified into higher- and lower-risk groups, with the lower-risk group showing improved PFS (HR = 4.7e−10, 95% CI: 0–inf, ) and ORR (75% vs. 0%, ). Conclusion. Several highly relevant potential biomarkers predictive of immunotherapy response in AGC patients have been identified in this research.

Background: Survival benefit of adjuvant radiotherapy for locally advanced gastric cancer following gastrectomy plus D2 lymphadenectomy has always been controversial. Esophagogastric junction (EGJ) adenocarcinoma, which is usually classified as gastric cancer in East Asia, often has a higher locoregional recurrence rate after operation because of its special anatomical characteristics. The aim of this study is to determine whether adjuvant radiotherapy can improve survival of locally advanced EGJ adenocarcinoma after D2 radical resection. Methods: In this phase III, randomized, open label, controlled trial, we plan to recruit 378 patients with Siewert type II and III adenocarcinoma of EGJ, who had undergone transabdominal radical surgery and D2 lymphadenectomy, and were divided into pathological stage IIB to IIIC. All patients will be randomized 1:1 to receive either adjuvant chemotherapy alone (control group) or adjuvant chemotherapy plus chemoradiotherapy (experimental group). Patients allocated to control group will receive eight cycles of S-1 plus oxaliplatin (SOX), while the experimental group will receive two cycles of SOX followed by 45-Gy RT combined with S-1 and four additional cycles of SOX. The primary endpoint is 3-year disease-free survival rate (DFS). The secondary endpoints are 3-year overall survival rate (OS), 3-year locoregional recurrence-free survival rate (LRFS), 3-year distant metastasis-free survival rate (DMFS), and quality of life (QoL). Discussion: In the past, the adjuvant treatment of EGJ adenocarcinoma needs to draw on the experience of esophageal adenocarcinoma or gastric adenocarcinoma. In this study, EGJ adenocarcinoma is considered as an independent disease, and the conclusion will provide evidence for optimal adjuvant therapy of locally advanced EGJ adenocarcinoma after D2 radical resection. Trial registration: ClinicalTrials.gov NCT03973008. Registered on 1 June 2019 (retrospectively registered), URL: https://clinicaltrials.gov/ct2/show/NCT03973008?term=NCT03973008&draw=2&rank=1

Background: A multicenter study on the DNA mismatch repair (MMR) genes enabled us to study the profiling of germline variants in MMR genes of colorectal cancer (CRC) patients with MMR deficiency (dMMR). The clinicopathological differences between Lynch syndrome (LS) patients and sporadic dMMR CRC patients were compared by Student’s t ‐test and χ ² test. The molecular profiling of germline variants in MMR genes in Chinese CRC patients with dMMR is clarified. Methods: A total of 326 CRC patients with dMMR were enrolled. Next‐generation sequencing (NGS) and Sanger sequencing were performed using tumor‐adjacent tissues of enrolled patients. Four MMR genes ( MLH1 , MSH2 , MSH6 , and PMS2 ) are included in the NGS panel. Results: A total of 113 germline variants were detected, including 81 pathogenic and likely pathogenic variants. The clinicopathologic differences between CRC patients with/without LS were observed in age, family history, lesion location, and dMMR patterns. The CRC cohort with IHC‐MSH6 negative alone shows the highest prevalence rate of LS. MLH1 was detected with the most germline variants. The mutational hotspot region of MLH1 is Exon 8, Exon 4 for MSH6 , Exon 11 for PMS2 , and Exon 7 for MSH2 . Several germline hotspots were labeled on each MMR gene sequence by fixed‐size bin analysis. In addition, some variants were novel discovered based on the presence or absence of the RS number and allele frequency record. Conclusions: Our study classified the clinicopathological features between sporadic CRC patients and LS patients. More importantly, the molecular profiling of the MMR gene germline variant was experimentally elucidated, which deepens the knowledge of MMR genes and provides a new perspective for the subsequent studies on the landscape of germline variants of Chinese LS patients.