Recent advancements highlight promising outcomes with immune checkpoint inhibitors (ICIs) when combined with concurrent chemoradiotherapy (CCRT) or chemotherapy in the treatment of locally advanced cervical cancer (LACC). This systematic review and meta-analysis aimed to assess the efficacy and safety of ICIs combined with CCRT/chemotherapy in patients with LACC. We searched PubMed, Embase, Cochrane and ClinicalTrials.gov for randomized controlled trials (RCTs) and non-RCTs assessing the efficacy and safety of ICIs plus CCRT/chemotherapy in patients with LACC. All analyses were performed in R software (v.4.4.0). Our systematic review and meta-analysis included 3 RCTs and 4 observational studies, corresponding to 1,250 patients. The 1-year progression-free survival (PFS) was 78% (95% confidence interval [CI]=75-80, I²=0%), while the 1-year overall survival (OS) reached 93% (95% CI=89-95, I²= 50%). The objective response rates were 88% (95% CI=74-95, I²=74%). We performed a comparative analysis of PFS and OS using data from the 2 RCTs. The results indicated that the ICI plus CCRT group had a significantly lower risk of disease progression or death compared to the CCRT group alone (PFS: hazard ratio [HR]=0.76, 95% CI=0.64-0.91, I²=4%; OS: HR=0.76, 95% CI=0.58-0.98, I²=0%), representing an approximate 25% reduction in risk. The analysis of grade ≥3 adverse events revealed the low incidences, with none exceeding 15%. Our findings suggest that ICIs are effective and safe to use with CCRT/chemotherapy in LACC patients. Further RCTs are needed to confirm these findings. International Prospective Register of Systematic Reviews Identifier: CRD42024576145.

Stereotactic body radiation therapy enhances therapeutic efficacy of immune checkpoint inhibitors by promoting the releasing of interferon-γ and interleukin-2

Thyroid transcription factor-1 (TTF-1) negativity is a poor prognostic factor for patients with lung adenocarcinoma. Platinum and pemetrexed have inferior therapeutic efficacy compared to other chemotherapy regimens in TTF-1-negative lung adenocarcinomas. However, the association between TTF-1 expression and efficacy of chemotherapy plus immune checkpoint inhibitors remains unclear. The aim of the study was to evaluate whether tumor expression of TTF-1 influence the efficacy of platinum and pemetrexed plus pembrolizumab in patients with advanced adenocarcinoma. This single-center retrospective study comprised patients with advanced lung adenocarcinoma treated with platinum and pemetrexed plus pembrolizumab and histologically evaluated for TTF-1 expression between January 2019 and June 2025. TTF-1 was detected in tumor tissue samples obtained by surgery, bronchoscopy, or computer tomography-guided biopsy using 8G7G3/1 antibody. We collected clinical medical records including TTF-1 expression and evaluated the relationship between TTF-1 expression and overall response rate, progression-free survival (PFS), and overall survival (OS). The Cox proportional hazards model was used to determine the association between patient background and survival outcomes. Of the 54 patients, 29 (53.7%) were TTF-1 positive. PFS (median, 12.6 vs. 13.1 months, p=0.92) and OS (median, 33.4 vs. 41.1 months, p=0.92) did not significantly differ between the TTF-1-positive and TTF-1-negative patients. Multivariate analysis revealed that performance status and primary tumor location were significantly associated with shorter OS, whereas TTF-1 negativity was not significantly associated with shorter OS. Platinum and pemetrexed combined with pembrolizumab remains an effective first-line treatment option for lung adenocarcinoma, regardless of TTF-1 expression.

Microbiota and cancer immunotherapy: Mechanisms, clinical implications, and precision therapeutics.

ABSTRACT The influence of COVID-19 vaccination on the efficacy and safety of immune checkpoint inhibitors (ICIs) in lung cancer treatment is not well understood. A cohort of 394 lung cancer patients treated with PD-1/PD-L1 inhibitors was analyzed. The incidence and types of irAEs were recorded, and the relationship between COVID-19 vaccination and progression-free survival (PFS) was assessed using univariate and multivariate analyses. Among the 394 patients, 44% (171 cases) experienced multiple irAEs, 29% (114 cases) had a single type of irAE, and 27% (108 cases) reported no adverse reactions. The most common irAEs included thyroid-related events (hypothyroidism: 18%, hyperthyroidism: 11%), skin toxicity (16%), cardiovascular toxicity (14%), skeletal muscle toxicity (8%), glycemic endocrine toxicity (7%), and pneumonia (6%). COVID-19 vaccination was associated with a decrease in the incidence of immune-related arthritis and myocarditis, while other irAEs such as pneumonia, dermatitis/rash, myositis, oculopathy, diabetes, colitis, nephritis, hypothyroidism, hyperthyroidism, hypophysitis, and transaminitis were unaffected. No significant correlation was found between COVID-19 vaccination and PFS in both univariate and multivariate analyses. COVID-19 vaccination does not increase the incidence of irAEs nor affect the PFS of lung cancer patients receiving ICIs treatment.

ABSTRACT The efficacy and safety of adding immune checkpoint inhibitors (ICIs) to neoadjuvant chemotherapy in patients with potentially resectable gastric cancer (GC) are uncertain. This study aimed to retrospectively evaluate the efficacy and safety of neoadjuvant ICIs plus chemotherapy in patients with potentially resectable GC. We retrospectively collected clinical data from patients with potentially resectable GC who received neoadjuvant treatment followed by gastrectomy at the Affiliated Hospital of Qingdao University from 2021 to 2023. The primary aim of this study was to investigate the differences in pathological tumor response (tumor regression grade, TRG) between neoadjuvant programmed cell death-(ligand)1 [PD-(L)1] blockade plus chemotherapy [neoadjuvant immunotherapy (IO) group] and chemotherapy alone (neoadjuvant chemotherapy group). Event-free survival (EFS) and treatment-related adverse events (TRAEs) were also observed. A total of 220 patients were retrospectively included in the analysis, among whom 96 (43.6%) received PD-(L)1 blockade plus chemotherapy as neoadjuvant treatment, and 124 (56.4%) received neoadjuvant chemotherapy. Higher pathological complete response (pCR) rate (21 of 96, 21.9% vs. 9 of 124, 7.2%, P = .004) and TRG0/1 rate (36 of 96, 37.5% vs. 22 of 124, 17.7%, P = .001) were detected in the neoadjuvant IO group. By the last follow-up, the median EFS time had not been reached in the two groups. The combined regimen of PD-(L)1 blockade plus chemotherapy was well-tolerated. In patients with potentially resectable GC, neoadjuvant ICIs plus chemotherapy resulted in higher pCR rates than did neoadjuvant chemotherapy alone. However, the difference in EFS rates was not statistically significant.

Deficiency in DNA mismatch repair (dMMR) is a common pathway of carcinogenesis across different tumor types and confers a characteristic microsatellite instability-high (MSI-H) molecular phenotype. The MSI-H/dMMR phenotype may arise from an inherited pathogenic variant in the context of Lynch syndrome and is most frequently observed in endometrial, colorectal, and gastric cancers. MSI-H/dMMR is a major predictive biomarker for the efficacy of immune-checkpoint inhibitors (ICIs). Following the approval of ICIs for metastatic disease, these drugs are now being evaluated in localized disease settings. In this review, we provide an overview of current knowledge regarding the use of ICIs as neoadjuvant therapy and as a part of immuno-ablative, surgery-sparing strategies, with a focus on Lynch-related cancers. Finally, we address the diagnosis, monitoring, and prevention challenges raised by these de-escalation strategies.

Gastric cancer (GC) is one of the most common and deadly types of cancer worldwide. In China, it is the most frequently occurring digestive tract tumour. Compared to traditional chemotherapeutic regimens centred on platinum and fluorouracil, immunotherapy has become one of the most important treatments for gastric cancer. Immune checkpoint inhibitors (ICIs) have the potential to benefit patients in the long term, but their development is limited by a high rate of resistance. To improve the efficacy of ICIs, it is important to understand the resistance mechanism in GC patients. In this paper, we review the resistance mechanisms of ICI in gastric cancer patients from four aspects: tumour immunity, immunosuppressed TME, tumour cells, and microbial populations.Additionally, we discuss new strategies and ideas to address ICI resistance in gastric cancer patients.

Immune checkpoint inhibitors (ICIs) have been approved for the treatment of various cancers; however, their clinical efficacy remains limited in many patients due to resistance mechanisms. One of the mechanisms underlying this resistance is the downregulated expression of programmed cell death-ligand 1 (PD-L1) caused by mutations that impair Janus kinase 1/2 (JAK1/2) function. Therefore, finding an alternative JAK-independent pathway to enhance PD-L1 expression would be highly valuable. In the present study, we found that the chemotherapeutic agents, SN-38 and cisplatin, upregulated the transcription factor interferon regulatory factor 1 (IRF1) and its downstream target PD-L1 in the melanoma cell line A2058. This induction occurred in a JAK-independent, but signal transducer and activator of transcription 1 (STAT1)-dependent manner, with STAT1 activation mediated by the tyrosine kinase Src. Furthermore, SN-38 upregulated PD-L1 expression not only in melanoma but also across multiple cancer types. These results suggest that DNA-damaging chemotherapeutic agents upregulate PD-L1 expression through a Src-STAT1-IRF1 signaling axis, potentially improving the therapeutic efficacy of ICIs, even in tumors with defective JAK signaling.

Identifying robust biomarkers to predict the efficacy of immune checkpoint inhibitors remains a key challenge in managing metastatic non-small cell lung cancer. This retrospective study aimed to investigate the prognostic and predictive value of complete blood count–derived inflammatory indices, in patients with metastatic non-small cell lung cancer receiving ICIs at the Sumy Regional Clinical Oncology Center between 2016 and 2024. A total of 105 patients were included, all of whom received either pembrolizumab or atezolizumab, with or without chemotherapy. Clinical data and baseline inflammatory indices were collected within seven days prior to treatment initiation. The indices analyzed included neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), systemic inflammation response index (SIRI), and lymphocyte-to-monocyte ratio (LMR). Receiver operating characteristic analysis was employed to determine optimal cut-off values, which were 3.6 for NLR, 1.5 for SIRI, 926.0 for SII, and 3.3 for LMR. Progression-free survival and overall survival were evaluated using the Kaplan–Meier method, with comparisons performed via log-rank test. Multivariate Cox proportional hazards regression was used to assess independent prognostic factors. A p-value <0.05 was considered statistically significant. The results demonstrated that among all analyzed markers, only NLR was significantly associated with overall survival. Patients with a low baseline NLR (<3.6) had a median overall survival of 19.7 months, compared to 10.0 months in those with high NLR (≥3.6), with a statistically significant difference (log-rank p=0.0191). Furthermore, multivariate Cox regression analysis confirmed NLR as an independent predictor of overall survival (HR=2.33, 95 % CI: 1.17–4.61, p=0.015). Other factors, including SII, SIRI, LMR, sex, therapy line, and treatment regimen, were not independently associated with survival outcomes. Although none of the inflammatory indices showed statistically significant impact on progression-free survival, a non-significant trend toward improved progression-free survival was noted in patients with low NLR (8.2 vs. 5.5 months, p=0.1084). In terms of treatment response, a significantly higher objective response rate was observed in the low NLR group (57.1 %) compared to the high NLR group (32.8 %, p=0.0213). Disease control rates, however, were comparable between the groups (85.7 % vs. 88.0 %, p=0.7515). These findings highlight the potential utility of baseline NLR as a non-invasive, cost-effective biomarker for prognostication and response prediction in metastatic non-small cell lung cancer patients undergoing immunotherapy. In contrast, SIRI, SII, and LMR did not demonstrate prognostic significance in this cohort. While the study’s retrospective and single-center nature limits external generalizability, the identification of NLR as an independent predictor of survival supports its integration into clinical workflows for early risk stratification. Further prospective, multicenter studies incorporating molecular and dynamic immunological parameters are warranted to validate and expand on these results.

Emerging evidence suggests that circadian timing influences the efficacy of immune checkpoint inhibitors (ICI), with morning infusions associated with improved therapeutic outcomes across various malignancies. However, the impact of ICI infusion timing on extensive-stage small cell lung cancer (ES-SCLC), a disease with poor prognosis and limited therapeutic advancements, remains unexplored. This retrospective study (LungTime-R02) analyzed 397 patients with ES-SCLC who received first-line anti-PD-L1 (atezolizumab or durvalumab) plus chemotherapy at our center between May 2019 and October 2023. The time of day of administration (ToDA) was calculated as the median infusion time for each patient's first four ICI treatment cycles. To assess its prognostic relevance, hazard ratios (HRs) of earlier progression or death were estimated across multiple ToDA thresholds (11:00-16:30). Propensity score matching (1:2) was applied to balance baseline characteristics. Of the 397 patients, the optimal ToDA cutoff for maximizing progression-free survival (PFS) benefit was identified as 15:00, with the lowest HR for PFS observed at this threshold. Patients who received immunochemotherapy before 15:00 exhibited significantly longer PFS and overall survival compared to those treated later, with results consistent across pooled and propensity score matching cohorts. Multivariable analysis confirmed early ToDA as an independent prognostic factor for both PFS (adjusted HR, 0.483; 95% CI, 0.357-0.654) and overall survival (adjusted HR, 0.373; 95% CI, 0.265-0.526). This study provides real-world evidence supporting the survival benefit of earlier immunochemotherapy administration in patients with ES-SCLC. These findings add to the growing body of knowledge on the clinical relevance of circadian timing in cancer treatment. Not applicable.

BackgroundMedications such as proton pump inhibitors (PPIs), antihistamines, and nonsteroidal anti‐inflammatory drugs have been linked to immune checkpoint inhibitor (ICI) efficacy in patients with non–small cell lung cancer (NSCLC), but these associations may reflect unmeasured confounding rather than true pharmacologic effects. This study evaluated whether commonly prescribed medications influence ICI outcomes, using a national patient sample and a negative control cohort.MethodsThe authors identified Veterans Health Administration (VHA) patients with stage IV NSCLC treated with first‐ or second‐line ICI therapy (n = 3739) or chemotherapy (n = 6585) from 2005 to 2023. Baseline use of 20 common medication classes and an immunomodulatory drug score were assessed. Propensity‐weighted Cox regression evaluated associations between each medication class and overall survival (OS) or time‐to‐next treatment (TTNT) in the ICI group. For any medication with a nominally significant association (p < .05), the same analysis was repeated in the chemotherapy group to test for nonspecific effects.ResultsAfter propensity weighting, 14 of 20 medication classes showed no association with OS or TTNT in the ICI cohort. Loop diuretics, anticoagulants, opioids, penicillin antibiotics, and fluoroquinolone antibiotics were associated with worse outcomes, but similar effects were seen in the chemotherapy group. A higher immunomodulatory drug score was also associated with inferior outcomes among ICI patients, but this association was likewise present in the chemotherapy cohort.ConclusionIn this study, commonly prescribed medications did not appear to alter ICI efficacy in stage IV NSCLC. Prior associations reported in the literature may be attributable to unmeasured confounding rather than true drug–immunotherapy interactions.

Background/Objectives: Colorectal cancer (CRC) is the second leading cause of cancer-related death in the US. The presence of deficient DNA mismatch repair and microsatellite instability (dMMR/MSI) in CRC is linked to responses to immune checkpoint inhibitors (ICIs). This study investigates the impact of metformin on the tumor microenvironment (TME) and clinical outcomes of patients with dMMR/MSI CRC treated with ICIs, aiming to better understand its potential role in enhancing ICI efficacy. Methods: Of 25,011 CRC patients in Caris database, 47 received both metformin and ICI therapy (Met-ICI group), and 475 patients received ICI therapy alone (ICI group). Samples underwent genomic or transcriptome sequencing at Caris Life Sciences. Immune cell fractions were estimated using quanTIseq. Univariate and multivariate survival analyses were conducted using the Cox proportional model. Results: The TME analysis of CRC patient samples revealed that TMB-High (≥10 mut/Mb) was more prevalent in the "ICI" group compared to the "Met-ICI" group (99.1% vs. 95.6%, p = 0.036). Mutation rates for most genes between the two groups were similar, but CIC gene mutations were more common in the "ICI" group than in the "Met-ICI" group (23.2% vs. 4.8%, p = 0.006). No significant differences were observed in the PD-L1 positivity rate or immune checkpoint gene expression (including IDO1, IFNG, TIM3, and CTLA4). M1 macrophages and neutrophils showed the highest infiltration among immune cells. However, the fractions of infiltrated immune cells were similar between the two cohorts. Univariate and multivariate analyses showed that there was no significant difference in patient survival between "ICI" and "Met-ICI" cohorts. Conclusions: In this retrospective analysis of real-world clinical outcomes, the concurrent use of metformin with ICIs in patients with dMMR/MSI CRC did not reveal an impact on clinical outcomes.

Immune checkpoint inhibitors (ICIs) have shown limited efficacy in unselected patients with metastatic castration-resistant prostate cancer (mCRPC). However, ICIs are approved for biomarker-defined subsets: microsatellite instability-high (MSI-H) and/or high tumor mutational burden (TMB-H). However, the efficacy of ICIs in TMB-H but not MSI-H disease remains unclear, and limited data exists evaluating ICI outcomes associated with blood-based MSI (bMSI) in mCRPC. This study used the US-based deidentified Flatiron Health-Foundation Medicine prostate cancer Clinico-Genomic Database (FH-FMI CGDB). Patients with tissue-assessed MSI (tMSI) and TMB (tTMB) status by an algorithm supporting an FDA-approved CDx for pembrolizumab were included if treated with single-agent ICI. Separately, outcomes on ICI associated with or bMSI were assessed. included if treated with single-agent ICI or taxane. Among 2,965 patients with mCRPC, tMSI-H (3.2%) was nearly always also tTMB≥10 mut/Mb (4.7%). In 84 ICI-treated patients, TTNT and OS were more favorable in tMSI-H with any TMB (TTNT HR: 0.18, 95%CI: 0.09-0.37 and OS HR: 0.32, 95%CI: 0.15-0.66) and tTMB≥10 without tMSI-H (TTNT HR: 0.18, 95%CI: 0.04-0.48 and OS HR: 0.20, 95%CI: 0.05-0.77) compared to tTMB < 10 without tMSI-H group. In intra-patient assessments, patients with tTMB≥10 had more favorable TTNT with subsequent ICI vs. prior taxane. Detection of bMSI-H was associated with more favorable TTNT on ICI (HR: 0.34, 95%CI: 0.14-0.83) and OS (HR: 0.21, 95%CI: 0.06-0.75) when tumor fraction ≥1%. These findings add support for tTMB and tMSI in predicting ICI monotherapy benefit in mCRPC and provide evidence supporting bMSI testing when tissue is unavailable.

Efficacy and safety of immune checkpoint inhibitors combined with anti-angiogenic agents compared to sorafenib or lenvatinib in the treatment of unresectable or advanced hepatocellular carcinoma a pairwise meta-analysis of randomized controlled trials.

Chemo-immunotherapy is the current standard of care for extensive-stage small cell lung cancer (ES-SCLC), but interpreting hazard ratios (HRs) from Cox models can be challenging when immune checkpoint inhibitors (ICIs) produce early crossing or delayed separation of Kaplan-Meier (KM) curves. Restricted mean survival time (RMST) and restricted mean time lost (RMTL) have emerged as alternative metrics that do not rely on the proportional hazards (PH) assumption. We conducted a systematic review and meta-analysis using reconstructed individual patient data (IPD) from phase III trials comparing ICIs to standard chemotherapy in the first-line setting for ES-SCLC. KM curves were digitized using the IPDfromKM R package version 4.3.2. to reconstruct pseudo-individual patient data, from which HRs, RMSTs, and RMTLs were derived. Seven trials comprising 1,766 patients were included. The pooled HR for progression-free survival (PFS) was 0.67 (95% confidence interval (CI): 0.59-0.76) with an RMST gain of 1.84 months and RMTL reduction of 1.84 months. The pooled HR for overall survival (OS) was 0.73 (95% CI: 0.68-0.79) with an RMST gain of 1.98 months and RMTL reduction of 1.97 months. PH violations were more frequently observed in PFS than OS. While HRs, RMSTs, and RMTLs were generally consistent, discrepancies in some trials underscore the value of RMST and RMTL as complementary, clinically intuitive measures. Incorporating RMST and RMTL into future ES-SCLC trials may improve the interpretability of treatment effects beyond conventional Cox model estimates.

Sex-differential responses to immune checkpoint inhibitors across the disease continuum unified by tumor mutational burden.

To assess the efficacy of immune checkpoint inhibitors (ICIs) combined with chemoradiotherapy and evaluate the prognostic value of peripheral inflammatory markers in elderly patients with inoperable esophageal squamous cell carcinoma (ESCC). A retrospective study of 124 elderly ESCC patients treated between 2021 and 2024. Patients were divided into immunotherapy and non-immunotherapy groups. Progression-free survival (PFS) was compared, and inflammatory markers were analyzed using Cox regression and ROC curves. Median PFS was significantly longer in the ICI group (13.7 vs. 10.9 months, P = 0.043). Immunotherapy was an independent protective factor for PFS. Post-treatment NLR and PNI were predictive of outcomes in the ICI group. Combining ICIs with chemoradiotherapy improves survival in elderly inoperable ESCC patients. NLR and PNI may serve as accessible biomarkers to guide immunotherapy.

SMC4 promotes immune evasion by inhibiting endogenous interferon signaling and upregulating PD-L1 expression in triple negative breast cancer.

Safety and Efficacy of Immune Checkpoint Inhibitors in Patients with Melanoma and Pre-existing Autoimmune Conditions: a Systematic Review and Meta-analysis