Tertiary lymphoid structures (TLSs) are ectopic immune cell clusters formed in nonlymphoid tissues affected by persistent inflammation, such as in cancer and prolonged infections. They have features of the structure and function of secondary lymphoid organs, featuring central CD20⁺ B cells, surrounded by CD3⁺ T cells, CD21⁺ follicular dendritic cells, and CD68⁺ macrophages, with a complex vascular system. TLS formation is governed by lymphotoxin-α1β2, TNF, and chemokines like CCL19, CCL21, and CXCL13, differing from secondary lymphoid organ development in developing later in life at sites of chronic inflammation. Their role in enhancing immune responses, particularly in the context of cancer, makes them a focal point in immunotherapy. This review discusses recent advances in TLS assessment that involves complex gene expression signatures, histological analysis, artificial intelligence, and spatial omics. The presence and maturity of TLS are associated with better outcomes in various cancers, acting as a biomarker for immunotherapy effectiveness. This review explores the structure, formation, and role of TLS in disease prognosis, including their roles in immunotherapy and non-immunotherapy treatments, highlighting a need to develop novel techniques for precise characterization of TLS as well as their significance as predictive biomarkers beyond traditional biomarkers.

Elevation of reactive oxygen species (ROS) levels is a general consequence of tumor cells’ response to treatment and may cause tumor cell death. Mechanisms by which tumor cells clear fatal ROS, thereby rescuing redox balance and entering a chemoresistant state, remain unclear. Here, we show that cysteine sulfenylation by ROS confers on aryl hydrocarbon receptor (AHR) the ability to dissociate from the heat shock protein 90 complex but to bind to the PPP1R3 family member PPP1R3C of the glycogen complex in drug-treated tumor cells, thus activating glycogen phosphorylase to initiate glycogenolysis and the subsequent pentose phosphate pathway, leading to NADPH production for ROS clearance and chemoresistance formation. We found that basic ROS levels were higher in chemoresistant cells than in chemosensitive cells, guaranteeing the rapid induction of AHR sulfenylation for the clearance of excess ROS. These findings reveal that AHR can act as an ROS sensor to mediate chemoresistance, thus providing a potential strategy to reverse chemoresistance in patients with cancer.

Background: Small cell carcinoma of the esophagus (SCCE) is an extremely rare and highly aggressive neuroendocrine malignancy with a strikingly poor prognosis. Given the great clinical successes of checkpoint immunotherapies, we explored the expression profile and clinical significance of programmed cell death-ligand 1 (PD-L1) and CD8⁺ T cell in SCCE for the first time. Materials and methods: Tumor-infiltrating immune cells (TIICs) and tumor cells in postoperative, whole tumor sections from 147 SCCE patients were stained for PD-LI expression. We also evaluated each patient’s Combined Positive Score (CPS). Multiplex immunofluorescence staining (CD3, CD20, CD68, and PD-L1) was introduced to clarify the location of PD-L1. CD8 density was analyzed by digital imaging and analysis of entire slides. Clinical outcomes were tested for correlations with both PD-L1 expression and CD8 density. Results: No patients had PD-L1 expressed in their tumor cells. PD-L1⁺ expression in TIICs was detected in 65 patients (44.2%) and 42 (28.6%) exhibited CPS positivity. Multiplex immunofluorescence staining demonstrated that most of the PD-L1 was expressed on the CD68⁺ monocytes/macrophages. PD-L1 expression in the TIICs and CPS was found to be correlated with paraffin block age, tumor length, macroscopic type, T stage, and increased overall survival (OS). Expression of PD-L1 in TIICs showed significantly prolonged relapse-free survival (RFS). Increasing CD8 densities were associated with increased PD-L1 expression (P _trend<0.0001). Multivariate regression confirmed that PD-L1 in TIICs and CD8 states were independent predictors of OS, and CD8 status were found to be independently predictive of RFS. A stratification based on PD-L1 and CD8 status was also significantly associated with both OS and RFS. Conclusion: Expression of PD-L1 was only detected in TIICs from approximately half of the patients with SCCEs. In SCCEs, PD-L1 and CD8 status are novel prognostic biomarkers and may inform the implementation of risk-related therapeutic strategies. SCCEs with higher CD8 infiltration also had higher expression of PD-L1, suggesting the development of resistance against adaptive immunity. These findings support the assertion that PD-L1/programmed cell death 1 inhibitors should be investigated in this rare malignancy.

Autophagy is an evolutionarily conserved lysosomal degradation pathway. In cancer, its role is paradoxical: it functions as a tumor-suppressive gatekeeper during initiation in part by preserving genomic stability, but it is frequently co-opted by established tumors to maintain metabolic fitness and therapeutic resistance. Early clinical efforts using broad, non-selective lysosomal inhibition (e.g., chloroquine) produced mixed outcomes and toxicities, prompting a paradigm shift toward modular, context-specific modulation.This review synthesizes the dynamic spatiotemporal evolution of autophagy in tumorigenesis, and characterizes it as an adaptable evolutionary trajectory governed by stress, tumor genotype, and microenvironmental context. We outline four conceptual pillars: genotype-defined modular networks, dynamic spatiotemporal adaptation, autophagy as an immunometabolic rheostat, and rational therapeutic modulation. Importantly, autophagy exerts cell-type-specific effects-promoting immune evasion in tumor cells while remaining indispensable for lymphocyte fitness. To address this paradox, we evaluate the transition from empirical global blockade to precision-guided intervention, including pathway-selective modulators, exploitation of selective vulnerabilities, and advanced targeted degradation technologies. Autophagy in cancer is a highly dynamic, context-dependent variable. Therapeutic control requires movement beyond universal flux inhibition toward pathway-specific, biomarker-guided interventions that match a tumor's distinct autophagic dependencies. Integration of dynamic monitoring with precise delivery systems may allow active modulation of the tumor microenvironment, transforming autophagy from a tumor resilience mechanism into an exploitable therapeutic vulnerability.

This study aimed to assess the benefits of immune checkpoint inhibitors (ICIs) for patients with low or negative PD‐L1 expression in advanced solid tumors. The study included cancers approved by the FDA for first‐line ICI therapy without PD‐L1 restrictions, incorporating phase III randomized clinical trials (RCTs) comparing immunotherapy with conventional care. Individual patient data of PD‐L1 low subgroup were retrieved from Kaplan–Meier (KM) curves using IPDfromKM and KMSubtraction. Pooled analysis employed KM and restricted mean survival time (RMST) analysis to assess ICI benefit. Totally, 40 RCTs with 27,060 patients were enrolled. No survival benefit for low PD‐L1 expression was observed in some cancers. In esophageal squamous cell carcinoma (ESCC), combined positive score (CPS) < 10 had significant OS benefit (HR = 0.82, p = 0.02; RMST‐D = 2.34 months); tumor proportion score (TPS) < 1% showed no OS improvement (HR = 0.87, p = 0.16, RMST‐D = 1.71 months). Human epidermal growth factor receptor 2 (HER2)‐negative gastroesophageal adenocarcinoma (GEA) had no OS benefit with CPS < 5, 1–4, and < 1, but significant benefits with CPS < 10 (HR = 0.87, p = 0.048; RMST‐D = 1.78 months, p = 0.038) and CPS 1–9 (HR = 0.83, p = 0.0085; RMST‐D = 2.21 months, p = 0.007). Patient‐level data indicate that ESCCs with TPS < 1% and HER2‐negative GEAs with CPS < 5 do not benefit from the addition of ICIs to conventional chemotherapy. More nuanced clinical trials and predictive biomarkers are warranted.