Programmed death-ligand 1 (PD-L1) is a critical immune checkpoint molecule that negatively regulates T-cell activation and serves as a characteristic marker of exhausted T cells in bacterial and viral infections. In this study, we found that Enterococcus faecalis (E. faecalis) infection modulated macrophage immune function under inflammatory conditions by upregulating PD-L1 expression. The aim of this study was to investigate the effect and potential regulatory mechanisms of E. faecalis and its virulence factor lipoteichoic acid (LTA) on the expression of PD-L1 in macrophages. RAW264.7 cells were treated with E. faecalis or LTA, respectively. Cellular immunofluorescence staining, flow cytometry, quantitative real time polymerase chain reaction (qRT-PCR) and Western blotting (WB) were employed to assess the expression of PD-L1 and endoplasmic reticulum (ER) stress-related proteins, including inositol-requiring enzyme 1 α (IRE1 α) and X-box binding protein 1 (XBP1), in macrophages. Following inhibition of the IRE1 α/XBP1 pathway and treatment with E. faecalis, qRT-PCR, flow cytometry, and WB were performed to detect the expression of PD-L1 and XBP1. Macrophage apoptosis was quantified by flow cytometry. Toll-like receptor 2 (TLR2) was knocked down using small interfering RNA (siRNA), and the expression of PD-L1, IRE1 α, and XBP1 in TLR2-silenced macrophages stimulated by E. faecalis was evaluated by qRT-PCR and WB. Statistical significance was analyzed using the Mann-Whitney test and Kruskal-Wallis test. The results demonstrated that E. faecalis and LTA significantly enhanced the expression of PD-L1, IRE1 α, and XBP1s in macrophages. Inhibition of the IRE1 α/XBP1 pathway reduced XBP1s and PD-L1 expression as well as apoptosis in E. faecalis-stimulated macrophages. TLR2 silencing decreased PD-L1, IRE1 α, and XBP1s expression levels in E. faecalis-stimulated macrophages. These findings reveal a novel mechanism by which E. faecalis induces persistent apical periodontitis and provide a foundation for further exploration of immune checkpoint molecules in the pathogenesis and treatment of this disease.

Patients with high-risk muscle-invasive bladder cancer (MIBC) remain at substantial risk of disease recurrence. Randomized phase 3 trials have evaluated adjuvant programmed cell death 1 (PD-1) inhibitors in this setting, but the magnitude and consistency of benefit across patient subgroups remain incompletely defined. We performed a systematic review and meta-analysis of randomized phase 3 trials comparing adjuvant PD-1 inhibitors with placebo or observation in patients with resected high-risk MIBC. HRs for disease-free survival (DFS) and overall survival (OS), as well as risk ratios for adverse events, were pooled using random-effects models. Prespecified subgroup analyses were conducted according to PD-L1 (programmed death-ligand 1) expression and prior receipt of cisplatin-based neoadjuvant chemotherapy. Two phase 3 trials encompassing patients treated with adjuvant nivolumab or pembrolizumab were included. Adjuvant PD-1 inhibitor therapy significantly improved DFS compared with control (pooled HR <1), with consistent benefit observed across PD-L1-defined subgroups and regardless of prior neoadjuvant cisplatin use. A favorable trend toward improved OS was observed, although survival data remain immature. Treatment was associated with a higher incidence of grade 3 or higher and immune-related adverse events compared with placebo or observation. Among patients with resected high-risk MIBC, adjuvant PD-1 inhibitor therapy significantly improves DFS with an acceptable safety profile. However, owing to the limited number of studies and short follow-up periods, these findings should be considered preliminary, and longer follow-up is required to confirm any potential OS benefit.

Clinical studies suggested that antibiotics (ABx) administration might increase esophagogastric junction adenocarcinoma risk, but the underlying mechanisms remain unclear. We previously demonstrated that the administration of a high-fat diet (HFD) and acid bile salts (ABS) to K19-Wnt1/C2mE mice might promote the metabolic-driven tumor growth at the squamocolumnar junction (SCJ) cooperatively with gut dysbiosis. To clarify whether ABx-induced dysbiosis promotes tumorigenesis, we evaluated the effects of HFD + ABS ± ABx treatment on tumor immune evasion in mice. In HFD + ABS + ABx-treated mice, SCJ tumor growth with increased tumor cell proliferation and infiltration of inflammatory cells positive for CD8, programmed cell death protein 1, and programmed cell death-ligand 1 (PD-L1) was observed, along with apoptosis suppression. Protein expressions of interferon-gamma (IFNγ) and phosphorylated signal transducer and activator of transcription (p-STAT) 3 were upregulated in the tumors of the HFD + ABS + ABx group, whose p-STAT1 expression was equivalent to that of the control group. The mice exhibited insulin resistance and metabolic endotoxemia, and metagenomic analysis of their ileal excrement revealed dysbiosis with a decrease in butyrate-producing bacteria and bacterial butanoate metabolism activity. Moreover, IFNγ stimulation of human-derived NUGC-4 cells increased the protein expression of PD-L1, p-STAT1, and p-STAT3, all of which decreased in response to STAT inhibitors. Transfection with small interfering RNA targeting STAT1 or STAT3 did not attenuate PD-L1 induction, which was inhibited by the combined knockdown. Therefore, oral HFD + ABS + ABx administration to K19-Wnt1/C2mE mice may promote SCJ tumors through tumor immune evasion via IFNγ-STAT1/STAT3-PD-L1 signaling, along with metabolic endotoxemia.NEW & NOTEWORTHY Coadministration of antibiotics with a high-fat diet and acid bile salts exacerbated dysbiosis, insulin resistance, and systemic inflammation, thereby promoting tumor progression via tumor immune evasion at the squamocolumnar junction (SCJ) in K19-Wnt1/C2mE mice. In the tumor, interferon-gamma-induced programmed death-ligand 1 through the activation of signal transducer and activator of transcription 1 (STAT1) and STAT3. Understanding the link between dysbiosis and tumor immunity might aid in the development of new immunotherapies for SCJ tumors.

A novel microtubule inhibitor modulates the myeloid PD-L1 expression, restores T cell effector function, and promotes apoptosis for effective suppression of colorectal cancer.

Pulmonary microbiota is a hidden link between lung cancer Development and microenvironment: Potential for future immune therapeutic strategies.

Targeting mir130b-IL-33-PD-L1 axis effectively inhibits esophageal squamous carcinoma progression.

Integrating PD-L1-targeted radioligand with protein degradation for precision tumor theranostics.

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cell carcinoma (RCC) with a poor prognosis in advanced stages. One of the major challenges in ccRCC treatment is the resistance to tyrosine kinase inhibitors or immune checkpoint inhibitors. Asparagine-linked glycosyltransferase 6 (ALG6) is a glycosyltransferase whose biological role in tumorigenesis remains largely unknown. Therefore, this study aims to investigate its function in ccRCC and its potential involvement in therapeutic resistance. We first analyzed 32 paired ccRCC and adjacent normal tissues from Shandong Provincial Hospital, correlating ALG6 expression with clinicopathological features (age, sex, tumor size, Tumor-Node-Metastasis [TNM] stage). In vitro, CCK-8, colony formation, and apoptosis assays were performed to assess the functional role of ALG6 in ccRCC cell lines. In vivo, a subcutaneous C57BL/6J mouse model and flow cytometry was used to evaluate the effect of ALG6 on the immune microenvironment and anti-PD-1 antibody sensitivity. In this study, we found that ALG6 was significantly overexpressed in ccRCC. Elevated ALG6 expression was positively correlated with tumor size and TNM stage, but negatively associated with overall survival in patients with ccRCC. Functional experiments demonstrated that downregulation of endogenous ALG6 markedly suppressed ccRCC cell viability and promoted apoptosis both in vitro and in vivo. Mechanistically, knockdown of ALG6 triggered endoplasmic reticulum (ER) stress, as evidenced by the upregulation of glucose-regulated protein 78 (GRP78) and activation of C/EBP homologous protein (CHOP) in ccRCC cells. Notably, knockdown of ALG6 significantly reduced programmed cell death ligand 1 (PD-L1) expression by inhibiting PD-L1 glycosylation and promoting its ubiquitin-mediated degradation. Furthermore, in vivo experiments demonstrated that ALG6 depletion destabilized PD-L1, enhanced antitumor T-cell immunity, and improved the therapeutic efficacy of anti-PD-1 treatment. This study demonstrates that downregulation of ALG6 induces ER stress-mediated apoptosis and enhances antitumor immunity by regulating PD-L1 expression in ccRCC. These findings suggest that ALG6 may serve as a potential therapeutic target for ccRCC.

Exploring the prognostic implications of programmed death-ligand 1 expression in canine nodal lymphoma: Insights from surface membrane expression, transcript amount and plasmatic levels.

The programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) is used as a biomarker to predict benefit from immune checkpoint blockade (ICB) in patients with non-small cell lung cancer (NSCLC). However, additional biomarkers are needed. The potential of kinase activity profiling of peripheral blood mononuclear cells (PBMCs) for predicting response to ICB was previously shown in a discovery study. The goal of this prospective study is to evaluate the predictive value of blood-based kinase profiling for ICB response in patients with NSCLC and to compare the performance and added value to TPS. Advanced stage patients with NSCLC, treated with anti-programmed cell death protein 1 ICB (±chemotherapy) were included in this multicenter study (N=210 patients). PBMCs were collected prior to ICB treatment and profiled using a peptide microarray with multiple kinase substrates (PamChip). Classification analysis was performed to discriminate between patients with or without progressive disease by Response Evaluation Criteria in Solid Tumors (RECIST) V.1.1 <24 weeks after treatment start. A predictive model was first established based on TPS and kinase activity profiles. Subsequently, the performance of the model was tested in a second (validation) cohort. In the validation cohort, a significantly higher progression-free survival (PFS) rate was observed for patients with predicted benefit than for patients without predicted benefit according to the kinome-based prediction model (HR=0.56, p=0.01), which tended better compared with TPS alone (HR=0.66, p=0.07). When the kinome-based model was combined with TPS, the difference in PFS between patients with and without predicted benefit was further increased (HR=0.38, p<0.001). PFS rates were also higher for patients with predicted benefit in subgroups with decreased PD-L1 expression (TPS <1% (HR=0.46, p=0.027) and TPS 1-50% (HR=0.20, p=0.005)). This study shows the predictive value of kinase activity profiling of PBMCs for ICB response in advanced NSCLC, which was superior compared with TPS. In particular, for patients with NSCLC with TPS <50%, combining TPS with the blood-based kinase test may identify patients with limited benefit from ICB. NTR7015/NL6828.

BackgroundResponse to anti-programmed cell death protein-1 (anti-PD-1) immunotherapy remains limited in patients with metastatic non-small cell lung cancer (NSCLC), whose tumors exhibit low or absent programmed death-ligand 1 (PD-L1) expression, and subsequent second-line therapy has poor efficacy. To address this limitation, we evaluated the efficacy and safety of combined ipilimumab and nivolumab (IPI/NIVO) with subablative radiotherapy (RT) in patients with metastatic NSCLC with negative or low PD-L1 expression, who had progressed on prior anti-PD-1 therapy.MethodsThis single-arm, prospective phase II trial aimed to enroll 30 evaluable patients with metastatic NSCLC exhibiting low (1–49%) or negative (<1%) PD-L1 tumor expression who had progressed after first-line anti-PD-1 therapy. Primary endpoints were safety, disease control rate (DCR), and objective response rate (ORR) at 6 and 12 weeks, assessed in non-irradiated tumor lesions. Treatment consisted of IPI 1 mg/kg every 6 weeks (Q6W) and NIVO 240 mg every 2 weeks for 6 weeks combined with subablative RT (3×8 Gy to 1–4 lesions). Thereafter, IPI 1 mg/kg Q6W and NIVO 360 mg every 3 weeks were continued.ResultsIn 31 patients of the intention-to-treat population, ORR was 7% and 10% at 6 and 12 weeks, and reached 29% as the best response. DCR was 58% and 39% at 6 and 12 weeks. Overall survival (OS) differed significantly by best response, with a median OS of 3.1, 13.5 and 22.5 months for progressive disease, stable disease and partial/complete response (p<0.001). Baseline sum of longest diameters, together with age, blood inflammatory markers and albumin levels, were prognostic of treatment response. All patients experienced treatment-related adverse events (AEs), with grade 3 as the highest severity in eight patients (26%). Immune-related AEs led to treatment discontinuation in five patients (16%). Early T-cell activation in peripheral blood samples (day 8) was detectable and more pronounced in responders than in progressors.ConclusionsIn patients with metastatic NSCLC and low or negative tumor PD-L1 expression, IPI/NIVO/RT was able to induce objective clinical responses in a subset of patients who had progressed after first-line anti-PD1 therapy. Treatment was associated with a strong T-cell activation, improved OS and an acceptable safety profile.Trial registration number2020–001097-29.

Background/Objective: Ultraviolet A and B (UVAB) radiation is a major environmental factor that induces DNA damage and upregulates programmed death-ligand 1 (PD-L1) expression in skin cells, thereby contributing to immune evasion and impaired tissue repair. This study evaluated the protective effects of two purified compounds, Cinnamtannin B1 (CTB-1) and Cinnamtannin D1 (CTD-1), as well as cinnamon extract, in UVAB-irradiated human keratinocyte HaCaT cells. Methods: HaCaT cells were exposed to low (20 kJ/m2 UVA, 1.3 kJ/m2 UVB), medium (30 kJ/m2 UVA, 2 kJ/m2 UVB), and high (40 kJ/m2 UVA, 2.7 kJ/m2 UVB) UVAB doses of UVAB radiation. Dose-dependent effects of CTB-1 and CTD-1 (0, 5, 10, 25, and 50 µg/ mL) and cinnamon extract (0, 5, 10, 50, and 100 µg/mL), as well as time-dependent effects (12, 24, and 72 h), were evaluated by measuring PD-L1 expression, cell viability, and DNA damage. Results: CTD-1 was the most effective compound, significantly reducing UVAB-induced PD-L1 expression and DNA double-strand breaks without compromising cell viability. CTB-1 also demonstrated protective effects at specific doses and time points; however, higher concentrations reduced cell viability. Cinnamon extract was protective at low concentrations but cytotoxic at higher doses. Conclusions: CTD-1, CTB-1, and cinnamon extract attenuated UVAB-induced cellular damage in HaCaT cells, with CTD-1 demonstrating the most favorable protective profile. These findings support the potential of cinnamon-derived compounds as therapeutic candidates for preventing UVAB-induced skin damage and immune dysregulation.

An immunosuppressive microenvironment driven by tumor and stromal cells expressing programmed death-ligand 1 (PD-L1) contributes to immune evasion and poor prognosis in cholangiocarcinoma. Although antibodies to PD-L1 are used clinically, their benefit is limited by immune exclusion within the local microenvironment. To overcome this, we evaluated engineered T cells directed toward PD-L1 that simultaneously target tumor cells and the immunosuppressive microenvironment. Human donor T cells were transduced with a lentiviral vector encoding a chimeric antigen receptor (CAR) consisting of an anti-PD-L1 scFv, CD4 transmembrane domain, and 4-1BB/CD3ζ signaling domain. The antitumor efficacy of these CAR-T cells was assessed in a murine orthotopic tumor model, and their specificity and effect were validated in human malignant cholangiocytes with varying PD-L1 expression. PD-L1 CAR-T cells retained T cell identity, demonstrated antigen-specific cytotoxicity, and effectively reduced tumor burden in vivo. Cytotoxicity was abrogated in PD-L1 knockout cells, confirming target specificity. PD-L1 CAR-T cells significantly reduced tumor cell viability within multicellular spheroids. Gemcitabine pretreatment upregulated PD-L1 expression and enhanced CAR-T-mediated cytotoxicity. These findings demonstrate the feasibility of second-generation PD-L1 CAR-T cells, demonstrating preclinical efficacy and specificity, and validating a therapeutic strategy that targets the tumor microenvironment for these challenging cancers.

Radiotherapy (RT) efficacy is limited by RT-induced immune resistance. Here we show that RT upregulates programmed death ligand 1 (PD-L1) on senescent tumor cells (STCs) via bromodomain-containing protein 4 (BRD4) signaling, thereby promoting immune evasion. To counter this, we develop POLY-Senolytic, a polymeric senolytic nanoparticle formed by conjugating an acid-responsive polymer to a peptide-based BRD4 PROteolysis-TArgeting Chimera via a reduction-cleavable disulfide bond. The POLY-Senolytic is activated in the acidic and reductive intracellular environment of tumor cells, leading to BRD4 degradation, suppression of RT-induced PD-L1 expression and enhanced immune clearance of STCs. Combined with RT, the POLY-Senolytic suppresses tumor growth and metastasis in orthotopic mouse models of pancreatic and breast tumors. We further engineer a β-galactosidase-responsive POLY-Tracker for real-time monitoring of senolytic therapy. Together, this study identifies an RT-driven BRD4-PD-L1 axis in STCs that promotes immune resistance and provides a practical strategy to eliminate and track them.

Programmed death-ligand 1 (PD-L1) is highly expressed in tumour cells and the tumour microenvironment, mediates tumour immune evasion, and is a key target for cancer immunotherapy. Immunohistochemistry (IHC), as a conventional method for PD-L1 detection, has limitations such as invasiveness, temporal and spatial heterogeneity, and an inability to provide dynamic monitoring. In contrast, PD-L1-targeted molecular imaging enables non-invasive, quantitative, and whole-body visual assessment of PD-L1 expression, offering a precise tool for patient selection, treatment response prediction and dynamic monitoring in immunotherapy, and has thus become a focal point in precision oncology research. This paper systematically reviews the development trajectory of PD-L1-targeting radiotracers, including monoclonal antibodies, peptides, nanobodies, aptamers and small molecules. It summarises the targeting performance, pharmacokinetics, imaging efficacy and safety in preclinical and clinical studies; compares the advantages and suitable applications of different types of tracers; analyses the challenges currently facing the field, such as the lack of evaluation standards, tumour heterogeneity, insufficient clinical translation and a scarcity of multicentre data; and offers a prospect on the standardisation of PD-L1-targeted molecular imaging, the integration of diagnosis and treatment, multimodal imaging and its promotion and application in primary care settings. To date, more than 40 PD-L1-targeting tracers have undergone preclinical or clinical validation, with non-invasive imaging demonstrated to be feasible in over 100 cancer patients; early data support further in-depth research and clinical translation in this field.

To investigate the effect of long non-coding RNA (LncRNA) differentiation antagonizing non-protein coding RNA (DANCR) on the immune microenvironment of glioma cells by regulating the miR-656/bone morphogenetic protein receptor type 1A (BMPR1A) axis. The expression levels of DANCR, miR-656 and BMPR1A in glioma cells were detected by quantitative real-time polymerase chain reaction (qRT-PCR). The U87 cells were transfected or co-transfected to form the following groups: sh-DANCR (transfected with sh-DANCR), overexpression (pcDNA 3.1) DANCR (transfected with pcDNA 3.1 DANCR), NC sh (transfected with negative control sh), pcDNA 3.1 (transfected with pcDNA 3.1 vector), sh-DANCR + miR-656 inhibitor (co-transfected with sh-DANCR and miR-656 inhibitor), sh-DANCR + NC inhibitor (co-transfected with sh-DANCR and NC inhibitor), sh-DANCR + pcDNA 3.1 BMPR1A (co-transfected with sh-DANCR and pcDNA 3.1 BMPR1A), and sh-DANCR + pcDNA 3.1 (co-transfected with sh-DANCR and pcDNA 3.1 BMPR1A). The untreated U87 cells were used as the blank group. The proliferation of U87 cells was detected by CCK-8; invasion and migration were detected by Transwell assay; apoptosis was detected by flow cytometry; the expression of DANCR, miR-656, and BMPR1A mRNA in cells was detected by qRT-PCR; the targeting relationship between DANCR and miR-656 was verified by dual-luciferase; and BMPR1A and immune escape factors [programmed death receptor 1 (PD-1) and programmed death-ligand 1 (PD-L1)] were detected by Western blot. The mRNA expressions of DANCR and BMPR1A in U87, A172, LN229 and U251 cells were significantly increased, while the expression of miR-656 was significantly decreased compared with those in NHA cells (P < 0.05). Compared with the blank group and sh-DANCR group, the proliferation rate, invasion, migration number, DANCR, BMPR1A mRNA, BMPR1A, PD-1, PD-L1 expression of U87 cells in the sh-DANCR group were obviously reduced, while the apoptosis rate and miR-656 expression were obviously increased (P < 0.05). Compared with the pcDNA 3.1 group, the proliferation rate, invasion, migration number, DANCR, BMPR1A mRNA, BMPR1A, PD-1, and PD-L1 expression of U87 cells in the pcDNA 3.1 DANCR group were obviously increased, while the apoptosis rate and miR-656 expression were obviously reduced (P < 0.05). Compared with the sh-DANCR +NC inhibitor group, the proliferation rate, invasion, migration number, BMPR1A mRNA, BMPR1A, PD-1, and PD-L1 expression of U87 cells in the sh-DANCR+miR-656 inhibitor group were obviously increased, and the apoptosis rate and miR-656 expression were obviously reduced (P < 0.05), while the expression of DANCR was not obvious (P>0.05). Compared with the sh-DANCR+pcDNA 3.1 group, the proliferation rate, invasion, migration number, BMPR1A mRNA, BMPR1A, PD-1, and PD-L1 expression of U87 cells in the sh-DANCR+pcDNA 3.1 BMPR1A group obviously increased, and the apoptosis rate obviously decreased (P < 0.05), while here was no statistically obvious difference in miR-656 expression and DANCR expression (P>0.05). DANCR and miR-656 had a targeted negative regulatory relationship. LncRNA DANCR improves the immune microenvironment of glioma cells and inhibits the malignant behavior development of cancer cells by regulating the miR-656/BMPR1A axis.

The bone marrow microenvironment in multiple myeloma (MM) is characterized by complex immune dysregulation involving multiple inhibitory pathways. Among these, the programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis contributes to T-cell dysfunction; However, its isolated role within this multifactorial network remains incompletely defined. This prospective observational study performed a cross-sectional immunophenotypic analysis of 39 newly diagnosed MM (NDMM) patients. PD-1 expression on T cells and PD-L1 expression on bone marrow (BM) plasma cells (PCs) were assessed using flow cytometry. Associations with clinical and laboratory parameters were analyzed using correlation analysis. PD-L1 mean fluorescence intensity (MFI) on PCs showed a positive correlation with BM T-cell percentage (r = 0.350, p = 0.029). PD-1 MFI on T cells correlated with total leukocytic count (TLC) (r = 0.326, p = 0.043). In International Staging System (ISS) stage III patients, PD-L1 expression on PC correlated with T cells% (r = 0.501, p = 0.018) and TLC (r = 0.427, p = 0.047), while PD-1 expression showed a strong positive correlation with TLC (r = 0.676, p = 0.001) and a negative correlation with age (r = - 0.492, p = 0.020). No significant association was observed with treatment response. These findings provide an exploratory description of PD-1/PD-L1 expression patterns within the BM microenvironment in MM. Only in advanced cases according to ISS, PD-L1 expression on PC was linked to BM T cells frequency. PD-1/PD-L1 expression patterns were not linked to treatment response.

Chemoimmunotherapy outperforms immunotherapy alone in advanced non-small cell lung cancer (NSCLC). However, current anatomical imaging and programmed death-ligand 1 (PD-L1) assessments are insufficient for early response prediction and do not directly capture treatment-induced immune effector function. Whether 68Ga-grazytracer PET/CT, which visualizes granzyme B as a marker of CD8+ T‑cell effector function, could assess early response and reveal potential differences between intravenous and bronchial arterial infusion (BAI)-based chemoimmunotherapy remains unknown. In this prospective study, 60 patients with advanced NSCLC receiving BAI-based (n = 28) or intravenous (n = 32) chemoimmunotherapy underwent 68Ga-grazytracer PET/CT after 1-2 treatment cycles. The primary endpoint was a 6-month objective response (iRECIST). Secondary endpoints compared immune activation between groups and the performance of 68Ga-grazytracer PET/CT for early response assessment versus conventional biomarkers (baseline tumor size [SLD], early anatomical change [ΔSLD], and PD-L1 expression). Statistical analyses included ROC curve analysis, logistic regression, and bootstrap internal validation. BAI-based chemoimmunotherapy showed higher 68Ga-grazytracer uptake (maximum standardized uptake value [SUVmax]: 2.86 ± 0.71 vs. 2.19 ± 0.80, P = 0.001) and objective response rate (60.71% vs. 34.38%, P = 0.04) than intravenous chemoimmunotherapy, suggesting a possible association with enhanced immune activation. The SUVmax demonstrated strong discriminative value for objective response (overall apparent AUC = 0.90; optimism-corrected = 0.89) and was the only independent early-response indicator, outperforming anatomical response metrics (SLD: AUC = 0.57; ΔSLD: AUC = 0.63) and PD-L1 expression (AUC = 0.45). The discriminative accuracy of the SUVmax was higher in the BAI cohort (apparent AUC = 0.99; corrected = 0.97) than in the intravenous cohort (apparent AUC = 0.83; corrected = 0.83). The corroborative performance of the tumor-to-blood ratio was not significantly different from that of SUVmax. 68Ga-grazytracer PET/CT is a promising early imaging biomarker for the response to chemoimmunotherapy in advanced NSCLC patients, particularly those receiving BAI-based regimens. Larger validation studies with uniform protocols are needed to validate these findings and assess its clinical utility. ChiCTR2500105792, the registration date is 2025-07-10, https://www.chictr.org.cn/showproj.html?proj=275165 .

The impact of KRAS mutation subtypes on treatment response to first-line immunochemotherapy in advanced lung adenocarcinoma (LUAD) remains uncertain. This study evaluated treatment efficacy across KRAS subtypes and examined the role of programmed death-ligand 1 (PD-L1) expression and co-mutations. We retrospectively analyzed 335 patients with advanced KRAS-mutant LUAD treated with first-line immunochemotherapy between 2018 and 2022 at two centers. Patients were categorized into G12A (n = 36), G12C (n = 116), G12D (n = 62), G12V (n = 56), and other subtypes (n = 65). PD-L1 tumor proportion score (TPS) was stratified as <1%, 1-49%, or ≥50%. Endpoints included progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR). Median PFS in the overall cohort was 8.6 months, with an ORR of 34.0% and a DCR of 87.8%. Median PFS did not differ significantly among KRAS subtypes (p = .617), nor within PD-L1 TPS groups: <1% (p = .740), 1-49% (p = .652), and ≥50% (p = .481). In the major subtypes (G12A, G12C, G12D, and G12V), PD-L1 expression showed no significant association with PFS. STK11 co-mutations were enriched in G12C, G12V, and other subtypes (p = .004) and correlated with shorter PFS (p = .006). In conclusion, first-line immunochemotherapy yields comparable efficacy across KRAS subtypes, independent of PD-L1 expression. Within the major subgroups (G12A, G12C, G12D, and G12V), PD-L1 levels were not predictive of PFS. STK11 co-mutations were enriched in G12C, G12V, and other subtypes and were associated with shorter PFS.

HSP10, HSP60, and HSP70 overexpression associates with PD-L1 upregulation and adverse outcomes in on-small cell lung cancer.