Recent single-arm studies involving neoadjuvant camrelizumab, a PD-1 inhibitor, plus chemotherapy for resectable locally advanced esophageal squamous cell carcinoma (LA-ESCC) have shown promising results. This multicenter, randomized, open-label phase 3 trial aimed to further assess the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy followed by adjuvant camrelizumab, compared to neoadjuvant chemotherapy alone. A total of 391 patients with resectable thoracic LA-ESCC (T1b-3N1-3M0 or T3N0M0) were stratified by clinical stage (I/II, III or IVA) and randomized in a 1:1:1 ratio to undergo two cycles of neoadjuvant therapy. Treatments included camrelizumab, albumin-bound paclitaxel and cisplatin (Cam+nab-TP group; n = 132); camrelizumab, paclitaxel and cisplatin (Cam+TP group; n = 130); and paclitaxel with cisplatin (TP group; n = 129), followed by surgical resection. Both the Cam+nab-TP and Cam+TP groups also received adjuvant camrelizumab. The dual primary endpoints were the rate of pathological complete response (pCR), as evaluated by a blind independent review committee, and event-free survival (EFS), as assessed by investigators. This study reports the final analysis of pCR rates. In the intention-to-treat population, the Cam+nab-TP and Cam+TP groups exhibited significantly higher pCR rates of 28.0% and 15.4%, respectively, compared to 4.7% in the TP group (Cam+nab-TP versus TP: difference 23.5%, 95% confidence interval (CI) 15.1–32.0, P < 0.0001; Cam+TP versus TP: difference 10.9%, 95% CI 3.7–18.1, P = 0.0034). The study met its primary endpoint of pCR; however, EFS is not yet mature. The incidence of grade ≥3 treatment-related adverse events during neoadjuvant treatment was 34.1% for the Cam+nab-TP group, 29.2% for the Cam+TP group and 28.8% for the TP group; the postoperative complication rates were 34.2%, 38.8% and 32.0%, respectively. Neoadjuvant camrelizumab plus chemotherapy demonstrated superior pCR rates compared to chemotherapy alone for LA-ESCC, with a tolerable safety profile. Chinese Clinical Trial Registry identifier: ChiCTR2000040034.

Background: Camrelizumab and chemotherapy demonstrated durable antitumor activity with a manageable safety profile as first-line treatment in patients with advanced esophageal squamous cell carcinoma (ESCC). This study aimed to evaluate the safety and efficacy of camrelizumab plus neoadjuvant chemotherapy, using pathologically complete response (pCR) as primary endpoint, in the treatment for locally advanced ESCC. Methods: Patients with locally advanced but resectable thoracic ESCC, staged as T1b-4a, N2-3 (≥3 stations), and M0 or M1 lymph node metastasis (confined to the supraclavicular lymph nodes) were enrolled. Eligible patients received intravenous camrelizumab (200 mg, day 1) plus nab-paclitaxel (100 mg/m², day 1, 8, 15) and carboplatin (area under curve of 5 mg/mL/min, day 1) of each 21-days cycle, for two cycles before surgery. The primary endpoint is pCR rate in the per-protocol population. Safety was assessed in the modified intention-to-treat population that was treated with at least one dose of camrelizumab. Results: From November 20, 2019 to December 22, 2020, 60 patients were enrolled. 55 (91.7%) patients completed the full two-cycle treatment successfully. 51 patients underwent surgery and R0 resection was achieved in 50 (98.0%) patients. pCR (ypT0N0) was identified in 20 (39.2%) patients and 5 (9.8%) patients had complete response of the primary tumor but residual disease in lymph nodes alone (ypT0N+). 58 patients (96.7%) had any-grade treatment-related adverse events (TRAEs), with the most common being leukocytopenia (86.7%). 34 patients (56.7%) had adverse events of grade 3 or worse, and one patient (1.7%) occurred a grade 5 adverse event. There was no in-hospital and postoperative 30-day as well as 90-day mortality. Conclusions: The robust antitumor activity of camrelizumab and chemotherapy was confirmed and demonstrated without unexpected safety signals. Our findings established camrelizumab and chemotherapy as a promising neoadjuvant treatment for locally advanced ESCC. Trial registration number: ChiCTR1900026240.

Objective: To compare perioperative and long-term outcomes of robot-assisted minimally invasive esophagectomy (RAMIE) and conventional minimally invasive esophagectomy (MIE) in the treatment for patients with esophageal squamous cell carcinoma (ESCC). Summary Background Data: RAMIE has emerged as an alternative to traditional open or thoracoscopic approaches. Efficacy and safety of RAMIE and MIE in the surgical treatment for ESCC remains uncertain given the lack of high-level clinical evidence. Methods: The RAMIE trial was designed as a prospective, multicenter, randomized, controlled clinical trial that compares the efficacy and safety of RAMIE and MIE in the treatment of resectable ESCC. From August 2017 to December 2019, eligible patients were randomly assigned to receive either RAMIE or MIE performed by experienced thoracic surgeons from 6 high-volume centers in China. Intent-to-treat analysis was performed. Results: Significantly shorter operation time was taken in RAMIE (203.8 vs 244.9 min, P<0.001). Compared with MIE, RAMIE showed improved efficiency of thoracic lymph node dissection in patients who received neoadjuvant therapy (15 vs 12, P = 0.016), as well as higher achievement rate of lymph node dissection along the left recurrent laryngeal nerve (79.5% vs 67.6%, P = 0.001). No difference was found in blood loss, conversion rate, and R0 resection. The 90-day mortality was 0.6% in each group. Overall complications were similar in RAMIE (48.6%) compared with MIE (41.8%) (RR, 1.16; 95% CI, 0.92–1.46; P = 0.196). Besides, the rate of major complications (Clavien-Dindo classification ≥ III) was also comparable (12.2% vs 10.2%, P = 0.551). RAMIE showed similar incidences of pulmonary complications (13.8% vs 14.7%; P = 0.812), anastomotic leakage (12.2% vs 11.3%; P = 0.801), and vocal cord paralysis (32.6% vs 27.1%, P = 0.258) to MIE. Conclusions: Early results demonstrate that both RAMIE and MIE are safe and feasible for the treatment of ESCC. RAMIE can achieve shorter operative duration and better lymph node dissection in patients who received neoadjuvant therapy. Long-term results are pending for further follow-up investigations. Trial Registration: ClinicalTrial.gov Identifier: NCT03094351.

Neoadjuvant immune checkpoint blockade (ICB) demonstrates promise in operable esophageal squamous cell carcinoma (ESCC), but lacks available efficacy biomarkers. Here, we perform single-cell RNA-sequencing of tumors from patients with ESCC undergoing neoadjuvant ICB, revealing a subset of exhausted CD8⁺ T cells expressing SPRY1 (CD8⁺ Tex-SPRY1) that displays a progenitor exhausted T cell (Tpex) phenotype and correlates with complete response to ICB. We validate CD8⁺ Tex-SPRY1 cells as an ICB-specific predictor of improved response and survival using independent ICB-/non-ICB cohorts and demonstrate that expression of SPRY1 in CD8⁺ T cells enforces Tpex phenotype and enhances ICB efficacy. Additionally, CD8⁺ Tex-SPRY1 cells contribute to proinflammatory phenotype of macrophages and functional state of B cells, which thereby promotes antitumor immunity by enhancing CD8⁺ T cell effector functions. Overall, our findings unravel progenitor-like CD8⁺ Tex-SPRY1 cells' role in effective responses to ICB for ESCC and inform mechanistic biomarkers for future individualized immunotherapy.

Posttranslational modifications add tremendous complexity to proteomes; however, gaps remain in knowledge regarding the function and regulatory mechanism of newly discovered lysine acylation modifications. Here, we compared a panel of non-histone lysine acylation patterns in metastasis models and clinical samples, and focused on 2-hydroxyisobutyrylation (Khib) due to its significant upregulation in cancer metastases. By the integration of systemic Khib proteome profiling in 20 paired primary esophageal tumor and metastatic tumor tissues with CRISPR/Cas9 functional screening, we identified N-acetyltransferase 10 (NAT10) as a substrate for Khib modification. We further showed that Khib modification at lysine 823 in NAT10 functionally contribute to metastasis. Mechanistically, NAT10 Khib modification enhances its interaction with deubiquitinase USP39, resulting in increased NAT10 protein stability. NAT10 in turn promotes metastasis by increasing NOTCH3 mRNA stability in an N4-acetylcytidine-dependent manner. Furthermore, we discovered a lead compound #7586-3507 that inhibited NAT10 Khib modification and showed efficacy in tumor models in vivo at a low concentration. Together, our findings bridge newly identified lysine acylation modifications with RNA modifications, thus providing novel insights into epigenetic regulation in human cancer. We propose that pharmacological inhibition of NAT10 K823 Khib modification constitutes a potential anti-metastasis strategy.

Stromal cells are physiologically essential components of the tumor microenvironment (TME) that mediates tumor development and therapeutic resistance. Development of a logical and unified system for stromal cell type identification and characterization of corresponding functional properties could help design antitumor strategies that target stromal cells. Here, we performed a pan-cancer analysis of 214,972 nonimmune stromal cells using single-cell RNA sequencing from 258 patients across 16 cancer types and analyzed spatial transcriptomics from 16 patients across seven cancer types, including six patients receiving anti–PD-1 treatment. This analysis uncovered distinct features of 39 stromal subsets across cancer types, including various functional modules, spatial locations, and clinical and therapeutic relevance. Tumor-associated PGF+ endothelial tip cells with elevated epithelial–mesenchymal transition features were enriched in immune-depleted TME and associated with poor prognosis. Fibrogenic and vascular pericytes (PC) derived from FABP4+ progenitors were two distinct tumor-associated PC subpopulations that strongly interacted with PGF+ tips, resulting in excess extracellular matrix (ECM) abundance and dysfunctional vasculature. Importantly, ECM-related cancer-associated fibroblasts enriched at the tumor boundary acted as a barrier to exclude immune cells, interacted with malignant cells to promote tumor progression, and regulated exhausted CD8+ T cells via immune checkpoint ligand–receptors (e.g., LGALS9/TIM-3) to promote immune escape. In addition, an interactive web-based tool (http://www.scpanstroma.yelab.site/) was developed for accessing, visualizing, and analyzing stromal data. Taken together, this study provides a systematic view of the highly heterogeneous stromal populations across cancer types and suggests future avenues for designing therapies to overcome the tumor-promoting functions of stromal cells. Significance: Comprehensive characterization of tumor-associated nonimmune stromal cells provides a robust resource for dissecting tumor microenvironment complexity and guiding stroma-targeted therapy development across multiple human cancer types.