Editorial: New advancement in tumor microenvironment remodeling and cancer therapy

tumor cells and the TME, influencing cancer progression (Sacco et al., 2021). The iron addiction phenotype, driven by reprogramming intracellular iron metabolism and interactions with immune cells, has dual effects, promoting cancer growth and suppressing antitumor immune functions (Cassim and Pouyssegur, 2019). The study by Battaglia, et al. revealed a significant correlation between iron density and PD-L1 expression in LUAD tissues. In vitro analyses on H460 and A549 LUAD cells showed the increased PD-L1 mRNA and protein levels in an iron-enriched microenvironment, mediated by reactive oxygen species (ROS)/c-Myc signaling pathway; iron-induced PD-L1 overexpression inhibited T cell activity, demonstrated by reduced IFN-γ release in co-culture system of tumor and T cells, emphasizing the impact of iron on immune modulation in LUAD. In TCGA LUAD datasets, the levels of transferrin receptor CD71, indicative of an ironaddicted phenotype, correlate with elevated PD-L1 mRNA. This study explores a novel association between high iron density and elevated PD-L1 expression in LUAD and the findings open a door for combinatorial strategies that consider TME iron levels to enhance the efficacy of anti-PD-1/PD-L1-based immune therapies for LUAD patients.ICTs have significantly transformed clinical outcomes for cancer patients, providing enduring clinical benefits, and even leading to a cure in a subset of individuals (Sharma et al., 2023). Cancer patient response to ICTs (e.g., pembrolizumab) varies across the tumor subtypes necessitates robust biomarkers for patient selection (Sharma et al., 2023). While PD-L1 expression and microsatellite instability (MSI-H) are FDA-approved indicators, tumor mutational burden (TMB), the number of somatic mutations per mega base of interrogated genomic sequence, is emerging as a promising biomarker in solid tumors (Sha et al., 2020;Singal et al., 2019). TMB varies across malignancies. The data from KEYNOTE-158 study showing TMB-high (≥10 mut/Mb) correlates with better pembrolizumab therapy outcomes in multiple cancer types, lead to FDA approval of pembrolizumab for TMB-high tumor subgroup (Marabelle et al., 2020). However, concerns arise regarding the TMB cutoff of 10 mut/Mb and its applicability beyond KEYNOTE-158 study. The study by MO., et al. aimed to statistically determine the optimal universal cutoff for defining TMB-high in the published clinical trials, predicting anti-PD-L1 therapy efficacy in diverse advanced solid tumors. By integrating MSK-IMPACT TMB data and objective response rate (ORR) across various solid cancer types, the authors identified 10 mut/Mb as the optimal cutoff, strongly correlated with PD-L1 blockade ORR. This study provides new universal TMB-high cutoff evidence in the support of KEYNOTE-158 study for guiding clinical decisions and addressing challenges associated with tumor-agnostic pembrolizumab approval in TMB-high cases.Oral squamous cell carcinoma (OSCC) is a highly malignant disease with an increasing incidence, which lacks effective treatments, urging the exploration of new therapeutic targets. The B7 family, a group of 10 structurally related, cell-surface protein ligands, including PD-L1 (B7-H1), encoded by CD274 gene, and inducible T cell costimulatory ligand (ICOSLG, B7-H2), encoded by CD275 gene, bind to receptors on lymphocytes that regulate adaptive immune responses in cancers (Ni and Dong, 2017). PD-L1 (B7-H1) plays a crucial role in immune escape in OSCC (Zhao et al., 2023). The association of ICOSLG expression levels with immunosuppression, tumor progression and prognosis of different solid cancer types such as gastric cancer (Chen et al., 2003), colorectal cancer (Cao et al., 2018) and glioblastoma (Iwata et al., 2020) In summary, all those publications within this Research Topic have improved our understanding of TME remodeling and cancer therapy interplay. Furthermore, these papers may make valuable contributions towards advancing the treatment options available for diverse cancers.