Cancer immunotherapy has revolutionized cancer treatment, and it relies heavily on the comprehensive understanding of the immune landscape of the tumor microenvironment (TME). Here, we obtain a detailed immune cell atlas of esophageal squamous cell carcinoma (ESCC) at single-cell resolution. Exhausted T and NK cells, regulatory T cells (Tregs), alternatively activated macrophages and tolerogenic dendritic cells are dominant in the TME. Transcriptional profiling coupled with T cell receptor (TCR) sequencing reveal lineage connections in T cell populations. CD8 T cells show continuous progression from pre-exhausted to exhausted T cells. While exhausted CD4, CD8 T and NK cells are major proliferative cell components in the TME, the crosstalk between macrophages and Tregs contributes to potential immunosuppression in the TME. Our results indicate several immunosuppressive mechanisms that may be simultaneously responsible for the failure of immuno-surveillance. Specific targeting of these immunosuppressive pathways may reactivate anti-tumor immune responses in ESCC.

Lung cancer is the leading cause of cancer-related death across the world. Unlike lung adenocarcinoma, patients with lung squamous cell carcinoma (LSCC) have not benefitted from targeted therapies. Although immunotherapy has significantly improved cancer patients’ outcomes, the relatively low response rate and severe adverse events hinder the clinical application of this promising treatment in LSCC. Therefore, it is of vital importance to have a better understanding of the mechanisms underlying the pathogenesis of LSCC as well as the inner connection among different signaling pathways, which will surely provide opportunities for more effective therapeutic interventions for LSCC. In this review, new insights were given about classical signaling pathways which have been proved in other cancer types but not in LSCC, including PI3K signaling pathway, VEGF/VEGFR signaling, and CDK4/6 pathway. Other signaling pathways which may have therapeutic potentials in LSCC were also discussed, including the FGFR1 pathway, EGFR pathway, and KEAP1/NRF2 pathway. Next, chromosome 3q, which harbors two key squamous differentiation markersSOX2andTP63is discussed as well as its related potential therapeutic targets. We also provided some progress of LSCC in epigenetic therapies and immune checkpoints blockade (ICB) therapies. Subsequently, we outlined some combination strategies of ICB therapies and other targeted therapies. Finally, prospects and challenges were given related to the exploration and application of novel therapeutic strategies for LSCC.

Objective: To determine whether RAL affects perioperative outcomes and long-term efficacy in NSCLC patients, compared with traditional VAL. Summary of Background Data: RAL is a promising treatment for NSCLC. However, its efficacy has not been fully evaluated. Methods: A single-center, open-labeled prospective randomized clinical trial was launched in May 2017 to compare the efficacy of RAL and VAL. By May 2020, 320 patients were enrolled. The perioperative results of RAL and VAL were compared. Results: The 320 enrolled patients were randomly assigned to the RAL group (n = 157) and the VAL group (n = 163). Perioperative outcomes were comparable between the 2 groups, including the length of hospital stay (P = 0.76) and the rate of postoperative complications (P = 0.45). No perioperative mortality occurred in either group. The total amount of chest tube drainage {830 mL [interquartile range (IQR), 550–1130 mL] vs 685 mL [IQR, 367.5–1160 mL], P = 0.007} and hospitalization costs [$12821 (IQR, $12145–$13924) vs $8009 (IQR, $7014–$9003), P < 0.001] were significantly higher in the RAL group. RAL group had a significantly higher number of LNs harvested [11 (IQR, 8–15) vs 10 (IQR, 8–13), P = 0.02], higher number of N1 LNs [6 (IQR, 4–8) vs 5 (IQR, 3–7), P = 0.005], and more LN stations examined [6 (IQR, 5–7) vs 5 (IQR, 4–6), P < 0.001]. Conclusions: Both RAL and VAL are safe and feasible for the treatment of NSCLC. RAL achieved similar perioperative outcomes, together with higher LN yield. Further follow-up investigations are required to evaluate the long-term efficacy of RAL. (ClinicalTrials.gov identifier: NCT03134534)

Objectives: To give a comprehensive review of the literature comparing perioperative outcomes and long-term survival with robotic-assisted minimally invasive esophagectomy (RAMIE) versus minimally invasive esophagectomy (MIE) for esophageal cancer. Background: Curative minimally invasive surgical treatment for esophageal cancer includes RAMIE and conventional MIE. It remains controversial whether RAMIE is comparable to MIE. Methods: This review was registered at the International Prospective Register of Systematic Reviews (CRD42021260963). A systematic search of databases was conducted. Perioperative outcomes and long-term survival were analyzed and subgroup analysis was conducted. Cumulative meta-analysis was performed to track therapeutic effectiveness. Results: Eighteen studies were included and a total of 2932 patients (92.88% squamous cell carcinoma, 29.83% neoadjuvant therapy, and 38.93% stage III-IV), 1418 underwent RAMIE and 1514 underwent MIE, were analyzed. The number of total lymph nodes (LNs) [23.35 (95% CI: 21.41–25.29) vs 21.98 (95% CI: 20.31–23.65); mean difference (MD) = 1.18; 95% CI: 0.06–2.30; P=0.04], abdominal LNs [9.05 (95% CI: 8.16–9.94) vs 7.75 (95% CI: 6.62–8.88); MD = 1.04; 95% CI: 0.19–1.89; P=0.02] and LNs along the left recurrent laryngeal nerve [1.74 (95% CI: 1.04–2.43) vs 1.34 (95% CI: 0.32–2.35); MD = 0.22; 95% CI: 0.09–0.35; P <0.001] were significantly higher in the RAMIE group. RAMIE is associated with a lower incidence of pneumonia [9.61% (95% CI: 7.38%–11.84%) vs 14.74% (95% CI: 11.62%–18.15%); odds ratio = 0.73; 95% CI: 0.58-0.93; P=0.01]. Meanwhile, other perioperative outcomes, such as operative time, blood loss, length of hospital stay, 30/90-day mortality, and R0 resection, showed no significant difference between the two groups. Regarding long-term survival, the 3-year overall survival was similar in the two groups, whereas patients undergoing RAMIE had a higher rate of 3-year disease-free survival compared with the MIE group [77.98% (95% CI: 72.77%–82.43%) vs 70.65% (95% CI: 63.87%–77.00%); odds ratio = 1.42; 95% CI: 1.11–1.83; P=0.006]. A cumulative meta-analysis conducted for each outcome demonstrated relatively stable effects in the two groups. Analyses of each subgroup showed similar overall outcomes. Conclusions: RAMIE is a safe and feasible alternative to MIE in the treatment of resectable esophageal cancer with comparable perioperative outcomes and seems to indicate a possible superiority in LNs dissection in the abdominal cavity, and LNs dissected along the left recurrent laryngeal nerve and 3-year disease-free survival in particular in esophageal squamous cell carcinoma. Further randomized studies are needed to better evaluate the long-term benefits of RAMIE compared with MIE.