Cancer Immunology, Immunotherapy[JOURNAL]
Sun
200 papers
Rituximab for severe immune checkpoint inhibitor-related adverse events: a multicenter case series.
Hermabessiere S, Jauzelon B, Marmain S … +9 more , Wauthier A, Witkowski Durand Viel P, Castille E, Padern G, Lamoureux A, Thomas QD, Quantin X, Maria ATJ, Coustal C
Cancer Immunol Immunother · 2026 Feb · PMID 41677859 · Full text
BACKGROUND: Immune checkpoint inhibitors (ICIs) can induce severe immune-related adverse events (irAEs) that are life-threatening and may be refractory to standard immunosuppressive therapy. Rituximab has emerged as a po...
BACKGROUND: Immune checkpoint inhibitors (ICIs) can induce severe immune-related adverse events (irAEs) that are life-threatening and may be refractory to standard immunosuppressive therapy. Rituximab has emerged as a potential treatment option, but evidence is limited. METHODS: We conducted a retrospective multicenter study including patients who received rituximab for severe ICI-related irAEs between 2018 and 2023. Clinical characteristics, type and severity of irAEs, previous immunosuppressive regimens, outcomes after rituximab, and oncologic status were collected. Overall survival was estimated from rituximab initiation. RESULTS: Eighteen patients were identified (median age 66 years, 55% male). irAEs were mainly neurological syndromes (n = 7), myositis and myocarditis (n = 6), and interstitial lung disease (n = 3). All events were grade 3-4 according to common terminology criteria for adverse events v5.0 and refractory to corticosteroids, often combined with additional immunosuppressants. Rituximab was administered as second- or third-line therapy. Clinical improvement was observed in 83% of patients, including complete resolution in 39%. After a median follow-up from rituximab initiation of 9.7 months (interquartile range [IQR] 5.1-23.9), seven patients (39%) died, but due to irAE only for three patients (17%). CONCLUSIONS: Rituximab appears to be an effective therapeutic option for selected severe ICI-related irAEs, particularly when conventional immunosuppressive regimens fail. These real-world data highlight the potential role of B-cell-targeted therapy in the management of complex irAEs and support further evaluation in prospective studies.
Stoking an anti-liver cancer immune response with cryoablation plus an intratumoral TLR9 agonist and dual checkpoint inhibitors.
Yang Y, Mandt T, Mittelstein D … +9 more , Das M, Wu P, Ghani MA, Illindala R, Steinmetz NF, Burgoyne AM, Berman Z, Webster N, Newton IG
Cancer Immunol Immunother · 2026 Feb · PMID 41677856 · Full text
The rising incidence of hepatocellular carcinoma (HCC) is partly driven by metabolic dysfunction-associated steatohepatitis (MASH). Recurrence after treatment is high, and advanced disease carries a poor prognosis. The i...
The rising incidence of hepatocellular carcinoma (HCC) is partly driven by metabolic dysfunction-associated steatohepatitis (MASH). Recurrence after treatment is high, and advanced disease carries a poor prognosis. The immunosuppressive tumor microenvironment (TME) in HCC limits the efficacy of immunotherapy, necessitating innovative approaches. To evaluate the efficacy of a novel therapeutic strategy designed to stimulate an antitumor immune response by combining cryoablation (Cryo) to release tumor antigen with an intratumoral immunostimulant (CpG) to facilitate immune recognition and dual immune checkpoint inhibitors (CPI) to disinhibit T cells. RIL-175 cells were orthotopically injected into two liver lobes in mice on a MASH-inducing diet. One tumor in each mouse was treated with partial Cryo, systemic dual CPI (anti-PD-1 and anti-CTLA-4), intratumoral TLR9 agonist CpG, or combinations thereof, while the second tumor was untreated. Tumor growth was monitored prior to and after ablation. Immune cell profiles and cytokine levels in both treated and untreated tumors were analyzed postmortem. The combined treatment of Cryo with CpG and dual CPI achieved the strongest tumor control and survival benefit. Cryo alone increased growth of the untreated tumor but addition of CpG and CPI reversed this effect. Immunologically, CPI primarily drove CTL expansion and PD-1 modulation, whereas CpG suppressed Tregs. Cryo monotherapy leads to immunosuppression, characterized by elevated Tregs, MDSCs, and PD-1 expression. Combining Cryo with CpG and CPI counteracts the inherent limitations of each therapy and enhances systemic anti-tumor immune responses.
Digital spatial profiling reveals additive effects of triple therapy on tumor microenvironment: anti-PD-L1, anti-VEGF, and PARP inhibition in mouse models.
Ueda A, Murakami R, Ishida K … +14 more , Hamada K, Ogura J, Kawahara S, Mise Y, Hosoe Y, Sugimoto M, Wakita D, Miyamoto T, Mizuno R, Taki M, Yamanoi K, Yamaguchi K, Hamanishi J, Mandai M
Cancer Immunol Immunother · 2026 Feb · PMID 41653296 · Full text
BACKGROUND: Immune checkpoint inhibitors show limited efficacy against immune-desert tumors, including ovarian cancer. We investigated triple therapy combining anti-programmed cell death-ligand 1 (PD-L1) antibody, anti-v...
BACKGROUND: Immune checkpoint inhibitors show limited efficacy against immune-desert tumors, including ovarian cancer. We investigated triple therapy combining anti-programmed cell death-ligand 1 (PD-L1) antibody, anti-vascular endothelial growth factor (VEGF) antibody, and Poly ADP-ribose polymerase inhibitor (PARPi) on tumor microenvironment using spatial profiling. METHODS: Two mouse models were employed: MC38 (immune-inflamed phenotype) and HM-1 (immune-desert phenotype). MC38 mice received anti-PD-L1 and anti-VEGF as monotherapy or dual combination. HM-1 mice received anti-PD-L1, anti-VEGF, and PARPi as monotherapy, dual combinations (anti-PD-L1 + anti-VEGF, anti-PD-L1 + PARPi, anti-VEGF + PARPi), or triple combination (anti-PD-L1 + anti-VEGF + PARPi). Spatial distribution of immune cells and the tumor microenvironment was analyzed using immunohistochemistry (CD8) and dual immunofluorescence (CD8/Granzyme B) with distance-based density quantification from tumor margins (0 to - 150, - 150 to - 300, - 300 to - 450 μm). High endothelial venule (HEV) formation was evaluated via CD31/MECA79 dual immunofluorescence. RESULTS: MC38 tumors responded to all treatments by day 10. Conversely, HM-1 tumors showed no response at day 10 but responded to two combination therapies by day 20: anti-PD-L1 + anti-VEGF (1.5-fold reduction, p = 0.04) and triple combination therapy (1.7-fold reduction, p = 0.03). In MC38, at - 150 to - 300 μm, anti-PD-L1 + anti-VEGF enhanced CD8 + Granzyme B + cells 1.9-fold versus Control (p = 0.01). In HM-1, at 0 to - 150 μm, triple therapy enhanced CD8 + Granzyme B + cells 2.8-fold (p = 0.02), while anti-PD-L1 + anti-VEGF increased CD8 + Granzyme B + cells 2.5-fold (p = 0.03). Both triple and anti-PD-L1 + anti-VEGF therapies induced CD31 + MECA79 + HEV formation (p < 0.01). CONCLUSIONS: Triple therapy may overcome immune-desert ovarian cancer through additive HEV formation, enhancing cytotoxic CD8 + T cell infiltration into the tumor.
CAR-T cells co-expressing IL-7 and CCL19 promote epitope spreading to enhance antitumor immunity.
Adachi K, Sakoda Y, Kaisho T … +1 more , Tamada K
Cancer Immunol Immunother · 2026 Feb · PMID 41653292 · Full text
Antigen heterogeneity remains a major obstacle to the effective application of chimeric antigen receptor (CAR)-T cell therapy in solid tumors. We investigated the potential of epitope spreading as a strategy to overcome...
Antigen heterogeneity remains a major obstacle to the effective application of chimeric antigen receptor (CAR)-T cell therapy in solid tumors. We investigated the potential of epitope spreading as a strategy to overcome this limitation and examined whether CAR-T cells concomitantly producing IL-7 and CCL19 (7 × 19 CAR-T cells) could act as potent inducers of epitope spreading, as well as the underlying mechanisms. We used a murine model inoculated with a mixture of cancer cell lines-genetically modified to express the CAR target antigen-and their respective parental lines lacking target expression. Following administration of 7 × 19 CAR-T cells, flow cytometry and peptide stimulation assays were performed to evaluate the induction of tumor antigen-specific T cells and dendritic cells within tumor-draining lymph nodes and tumor tissues. We also evaluated the antitumor efficacy of 7 × 19 CAR-T cells derived from an allogeneic donor and their capacity to induce epitope spreading in vivo and ex vivo. In multiple tumor mixture models, 7 × 19 CAR-T cells demonstrated marked antitumor activity and promoted epitope spreading in murine solid tumor models, enabling endogenous T cells to recognize and target tumor-associated antigens. This response was dependent on cross-presentation by defined dendritic cell subsets in both the tumor microenvironment and tumor-draining lymph nodes within 2 weeks of 7 × 19 CAR-T cell administration. Notably, 7 × 19 CAR-T cells derived from allogeneic donors also induced epitope spreading in tumor-bearing hosts, thereby increasing survival. The 7 × 19 CAR system is a promising strategy for overcoming antigen heterogeneity in solid tumors by promoting epitope spreading.
Radiotherapy enhances M1 macrophage immunogenic activity through IFNs induction and stimulation in TP53-wild type tumors.
Cheng CC, Yeh HZ, Sie ZL … +5 more , Wang CL, Peng CL, Ho AS, Wang CI, Chang CC
Cancer Immunol Immunother · 2026 Feb · PMID 41653234 · Full text
Radiotherapy (RT), widely employed in clinical practice to suppress tumor progression, exhibits an abscopal effect that enhances immunogenic activity to potentially benefit immunotherapeutic efficacy. However, the tumor...
Radiotherapy (RT), widely employed in clinical practice to suppress tumor progression, exhibits an abscopal effect that enhances immunogenic activity to potentially benefit immunotherapeutic efficacy. However, the tumor types most likely to exhibit such effects remain unclear. Since TP53-wild type tumors are sensitive to RT, we hypothesized and aimed to investigate whether these tumors are prone to RT-induced abscopal effects. Bioinformatic analyses with RNAseq were conducted to identify the differentially expressed genes. Next, quantitative polymerase chain reaction with flow cytometry was used to assess the potential mechanism. In liver hepatocellular carcinoma (LIHC), a cancer type with a 27% TP53 mutation (therefore 73% TP53-wild type), we noticed that p53 expression positively correlated with the 15 selective immunotherapy-associated genes. We consequently validated that the IFNγ-up-regulated genes in TP53-wild type A549 cells were correlated with better immunotherapeutic outcomes. In contrast, RT induced a distinct set of genes enriched in p53 signaling pathways to correlate with better survival in LIHC patients, but not with immunotherapeutic response. Even so, we found that RT specifically induced apoptosis in TP53-wild type HCT116 cells compared to TP53null HCT116 cells to significantly promote immune cell activation in vitro. We consequently demonstrated the major factors, including IFNα and IFNγ expression, induced by RT in TP53-wild type tumors potentially enhance M1 macrophage polarization, whereas these effects were absent in TP53null models. In conclusion, our findings demonstrate that RT specifically suppressed TP53-wild type tumors, leading to IFNs expression. The RT-mediated immunogenic activation was potentially derived from the RT-induced IFNs, which were speculated to contribute to M1 macrophage polarization and immunogenic activity. These results suggest TP53-wild type tumors may be ideal candidates for combining RT and immunotherapy in clinical settings.
High PD-1 expression in pre-treatment peripheral lymphocytes associated with poor immune checkpoint inhibitor response in patients with recurrent or metastatic head and neck squamous cell carcinoma.
Li SH, Huang WT
Cancer Immunol Immunother · 2026 Feb · PMID 41653201 · Full text
Programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade is the standard therapy for recurrent or metastatic head and neck squamous cell carcinoma (RMHNSCC), yet many patients exhibit poor r...
Programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) blockade is the standard therapy for recurrent or metastatic head and neck squamous cell carcinoma (RMHNSCC), yet many patients exhibit poor responses. Potential non-invasive biomarkers for predicting treatment response in RMHNSCC remain unclear. In this study, we collected blood samples from 47 RMHNSCC patients and 17 healthy controls. PD-1 expression was evaluated using 10-color flow cytometry before treatment. Subpopulations of peripheral blood lymphocytes (PBLs) were assessed at baseline, 2-3 weeks, and 6 weeks after the first anti-PD-1 immune checkpoint inhibitor (ICI) treatment. A total of 116 patient samples were used for longitudinal comparison of treatment-induced changes in lymphocyte subpopulations. Patients had higher PD-1+ PBL levels than healthy individuals (25.0% vs. 20.3%, P = 0.006). Those with PD-1+ PBLs ≥ 25% exhibited elevated T cell levels and higher frequencies of PD-1+lymphocyte subsets expressing CD38 and HLA-DR concurrently or CD56/CD16, alongside reduced NK cell levels before anti-PD1 therapy. The median progression-free survival (PFS) was 2.2 months, with an overall one-year PFS rate of 18%. The patients with PD-1+ PBLs ≥ 25% showed significantly poorer one-year PFS (7% vs. 29%, P = 0.039) and overall survival rates (20% vs. 50%, P = 0.018) than the opposite group. Comparing fold changes from baseline, the patients with PD-1+PBLs ≥ 25% showed significantly lower increases in CD4+CD38+HLA-DR +T cells (median: 1.15 vs. 1.66 at the first post-treatment test), and CD8+CD38 + HLA-DR + T cells (medians: 1.01 vs. 1.34 and 1.23 vs. 1.78 at the first and second post-treatment tests, respectively) compared to the opposing group. Our findings indicate that high PD-1 expression in PBLs predicts poor treatment outcomes for anti-PD-1 ICIs in patients with RMHNSCC. Dynamic immune monitoring can assist physicians in tailoring personalized therapeutic strategies.
Comparative efficacy of combination regimens based on interventional therapy and immune checkpoint inhibitors (ICIs) in patients with intermediate- and advanced-stage hepatocellular carcinoma: a systematic review, meta-analysis, and network meta-analysis.
Su J, Su Y, Mai R … +14 more , Gao X, Li S, Zeng D, Cen W, Huang Z, Li X, Zeng H, Li W, Zeng C, Wu T, Mo K, Ye J, Lin Y, Liang R
Cancer Immunol Immunother · 2026 Feb · PMID 41653198 · Full text
BACKGROUND: Combining interventional therapy with immune checkpoint inhibitors (ICIs) has shown potential benefits in hepatocellular carcinoma (HCC). However, comprehensive evidence on its efficacy and safety remains lim...
BACKGROUND: Combining interventional therapy with immune checkpoint inhibitors (ICIs) has shown potential benefits in hepatocellular carcinoma (HCC). However, comprehensive evidence on its efficacy and safety remains limited. METHODS: A systematic search of PubMed, Embase, Cochrane Library, and Web of Science was conducted to identify eligible studies for single-arm and Bayesian network meta-analyses (NMA). Progression-free survival (PFS) was the primary endpoint, while overall survival (OS), objective response rate (ORR), and grade ≥ 3 adverse events (AEs) were secondary outcomes (PROSPERO: CRD42024619661). FINDINGS: This study included 45 studies (n = 4,738), evaluating 14 distinct regimens. In single-arm analysis, transcatheter arterial chemoembolization (TACE) plus tyrosine-kinase inhibitor (TKI) plus tislelizumab [TACE-TKI-Tisle] yielded a pooled median PFS of 11.7 months (95% confidence interval [CI] 8.02-15.37), an ORR of 72% (95% CI 63-80%), and a grade ≥ 3 AE rate of 24% (95% CI 15-34%). NMA showed that TACE-TKI-Tisle and TACE-TKI-Camrelizumab (Camre) achieved significantly longer PFS than TACE-TKI or TACE alone. TACE-TKI-Toripalimab (Tori) showed OS benefits over TACE-TKI-Camre (HR = 0.43; 95% CI 0.20-0.95) and TACE-TKI-Pembrolizumab (Pembro) (HR = 0.32; 95% CI 0.13-0.81). Cumulative ranking via surface under the cumulative ranking curve (SUCRA) indicated that TACE-TKI-ICI achieved the highest efficacy ranking. TACE-TKI-Tisle and TACE-TKI-Tori ranked highest for PFS/ORR, with TACE-TKI-Tori ranking first for OS (SUCRA = 0.981). While TACE-TKI-ICI combinations were generally associated with more grade ≥ 3 AEs, TACE-TKI-Tisle ranked intermediately for safety (SUCRA = 0.426). CONCLUSION: TACE-TKI-ICI combinations show promising efficacy in HCC. TACE-TKI-Tisle offers balanced efficacy and safety, while TACE-TKI-Tori provides notable OS benefits, warranting further validation in prospective studies.
Effectiveness of ICI-ICI versus ICI-TKI combinations in patients with IMDC intermediate- and poor-risk metastatic renal cell carcinoma: a sub-analysis of the MEET-URO 33 study.
Maffezzoli M, Signori A, Acunzo A … +40 more , Buti S, Bosoni M, Verzoni E, Di Marco A, Lolli C, Di Napoli M, Fanelli M, Volta AD, Masini C, Roviello G, Iacovelli R, Mennitto A, Filippi R, Sorarù M, Formisano L, Guida A, Fantinel E, Messina C, Bonomi L, Scagliarini S, Nasso C, Chiellino S, Maiorano BA, Deppieri F, Cavo A, Conteduca V, Zai S, Zucali PA, Tucci M, Vignani F, La Russa F, Lombardo L, Caserta C, Paolieri F, Bertolotti F, Rescigno P, Banna GL, Fornarini G, Bimbatti D, Rebuzzi SE
Cancer Immunol Immunother · 2026 Feb · PMID 41632305 · Full text
BACKGROUND: Immune checkpoint inhibitor doublet (ICI-ICI) and ICI plus tyrosine kinase inhibitor (ICI-TKI) regimens are the cornerstone of treatment for metastatic renal cell carcinoma (mRCC), although no head-to-head co...
BACKGROUND: Immune checkpoint inhibitor doublet (ICI-ICI) and ICI plus tyrosine kinase inhibitor (ICI-TKI) regimens are the cornerstone of treatment for metastatic renal cell carcinoma (mRCC), although no head-to-head comparisons are currently available. This study aimed to compare the real-world effectiveness of ICI-ICI versus ICI-TKI combinations in patients with intermediate- and poor-risk mRCC according to International Metastatic RCC Database Consortium (IMDC). METHODS: The Meet-URO 33 study is a multicentre retrospective-prospective registry collecting real-world data on patients with mRCC. Multivariable logistic and Cox models were built for objective response rate (ORR), PFS and OS, with a propensity score (PS) adjustment for baseline imbalances. RESULTS: Among 1497 patients, 755 were intermediate-risk (199 ICI-ICI, 556 ICI-TKI) and 312 poor-risk (77 ICI-ICI, 212 ICI-TKI). Median follow-up was 14.2 months (8.0 months and 14.5 months in poor- and intermediate-risk subgroups, respectively). In poor-risk patients, median OS was 20.3 versus 12.9 months (HR 0.87, 95% CI 0.59-1.28, p = 0.49), and median PFS was 6.7 versus 8.7 months (HR 1.10, 95% CI 0.79-1.54, p = 0.53), for ICI-ICI versus ICI-TKI, respectively. In the intermediate-risk patients treated with ICI-ICI versus ICI-TKI, median OS was 37.8 versus 35.5 months (HR 1.08; 95% CI 0.77-1.50; p = 0.65), and median PFS was 17.8 versus 18.6 months (HR 1.29, 95% CI 1.00-1.66, p = 0.050). ORR was 42.9% versus 45.8% in poor-risk patients (OR 0.72, 95% CI 0.39-1.34, p = 0.303) and 48.1% versus 54.3% in intermediate-risk patients (OR 0.71, 95% CI 0.48-1.04, p = 0.075). CONCLUSIONS: No statistically significant differences in survival or response were observed between ICI-ICI and ICI-TKI combinations in patients with IMDC intermediate- and poor-risk mRCC.
IL-6 as a driver of bone invasion in IFIT2-depleted oral squamous cell carcinoma.
Lai KC, Hsieh CH, Wang CH … +4 more , Hsiao SY, Kao WC, Chao CC, Chen PC
Cancer Immunol Immunother · 2026 Jan · PMID 41619016 · Full text
Oral squamous cell carcinoma (OSCC), the most prevalent oral cancer, often exhibits local bone invasion. Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) has been identified as a tumor suppressor in OS...
Oral squamous cell carcinoma (OSCC), the most prevalent oral cancer, often exhibits local bone invasion. Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) has been identified as a tumor suppressor in OSCC, though its role in bone invasion remains unclear. This study aimed to investigate the involvement of IL-6 as a driver of bone invasion in OSCC with depleted IFIT2 expression and to evaluate the clinical relevance of IFIT2 and IL-6. IFIT2 knockdown significantly increased IL-6 mRNA and secretion levels in OSCC cells, indicating IFIT2's potential regulatory role in inflammation within the tumor microenvironment. Elevated IL-6 levels in IFIT2-depleted OSCC cells markedly enhanced osteoclast differentiation and bone resorption. Neutralizing IL-6 reversed these effects, confirming IL-6 as a key mediator of bone invasion in OSCC cells. These results indicate that IL-6 as driver of bone invasion in IFIT2-depleted OSCC cells. Clinically, serum IL-6 concentrations were significantly higher in patients with advanced-stage tumors (T4) compared to early stages (T1-3; p = 0.027), supporting IL-6's role as a progression marker. Stage IV OSCC patients exhibited higher IL-6 levels compared to stages I-III, further substantiating IL-6's prognostic significance in advanced OSCC (p = 0.043). Serum IL-6 positively correlated with pro-tumorigenic cytokines, including VEGF-α and G-CSF. Notably, a high IL-6/IFIT2 ratio was associated with reduced median survival among OSCC patients. These findings indicate that IFIT2 depletion enhances OSCC-induced bone invasion predominantly through IL-6-mediated osteoclast activation, establishing the IL-6/IFIT2 axis as a critical regulator of OSCC progression and metastasis.
Comparison of real-world efficacy and safety of nivolumab plus ipilimumab or pembrolizumab combined with platinum-based chemotherapy as first-line treatment for advanced non-small cell lung cancer in a German population.
Weber M, Freiherr von Hammerstein-Equord A, Weinreich M … +2 more , Andreas S, Rittmeyer A
Cancer Immunol Immunother · 2026 Jan · PMID 41619000 · Full text
INTRODUCTION: In advanced non-small cell lung cancer (NSCLC), nivolumab plus ipilimumab with platinum-based chemotherapy (NIC) and pembrolizumab with platinum-based chemotherapy (PC) are commonly used treatment options....
INTRODUCTION: In advanced non-small cell lung cancer (NSCLC), nivolumab plus ipilimumab with platinum-based chemotherapy (NIC) and pembrolizumab with platinum-based chemotherapy (PC) are commonly used treatment options. We conducted a single-center retrospective analysis comparing the two options under real-world conditions in Germany. METHODS: We collected data from patients whose treatment was initiated between July 2018 and June 2023. Primary endpoints were overall survival and safety. Categorical data were compared using the chi-squared test or Fisher's exact test. Overall survival was compared using the Kaplan-Meier method and the log-rank test. RESULTS: 200 patients, 77 treated with NIC and 123 treated with PC, were included. Baseline characteristics were unbalanced with significantly more older, squamous, and PD-L1-negative cases in the NIC group. Median overall survival (OS) and time to treatment discontinuation (TTD) were not significantly different in the NIC and PC groups (13.6 vs. 14.1 months / 5.8 vs. 6.2 months). Clinically significant adverse events (AEsi), related treatment discontinuations, and treatment-related deaths also did not differ significantly (p = 0.885/p = 1.000/p = 0.709). There were more immune-related AEsi in the NIC group (p = 0.001) and more chemo-related AEsi in the PC group (p < 0.001). CONCLUSIONS: NIC and PC seem to be equally supportable options in the treatment of advanced NSCLC. Further analyses are needed to validate our findings.
Photothermal therapy synergizes with CD47 blockade by inducing calreticulin exposure and remodeling the tumor extracellular matrix in oral squamous cell carcinoma.
Tang Q, Hu L, Li W … +8 more , Qin T, Hu D, Ren M, Zheng X, Sugimura R, Zhou X, Cheng L, Chen J
Cancer Immunol Immunother · 2026 Jan · PMID 41603985 · Full text
BACKGROUND: Oral squamous cell carcinoma (OSCC) overexpresses CD47, enabling immune evasion via a "don't eat me" signal to macrophages. Although CD47 blockade shows promise, its efficacy is limited due to a lack of "eat...
BACKGROUND: Oral squamous cell carcinoma (OSCC) overexpresses CD47, enabling immune evasion via a "don't eat me" signal to macrophages. Although CD47 blockade shows promise, its efficacy is limited due to a lack of "eat me" signal and contact between macrophages and tumor cells. OBJECTIVES: This study aimed to evaluate the synergistic anti-tumor effect of combining photothermal therapy (PTT) with CD47 blockade in OSCC and elucidate the underlying mechanisms. METHODS: In vitro phagocytosis was assessed by flow cytometry. In vivo anti-tumor efficacy was measured by tumor growth inhibition. Mechanistic studies included detection of immunogenic cell death (ICD) markers (ATP, HMGB1, calreticulin (CRT)), confocal microscopy for CRT-macrophage co-localization, analysis of ECM component expression, and immunofluorescence for macrophage infiltration. RESULTS: The combination of PTT and CD47 blockade significantly enhanced macrophage phagocytosis in vitro and strongly inhibited tumor growth in vivo. PTT induced ICD, as evidenced by the release of ATP and HMGB1, and the exposure of CRT on the cell membrane. Confocal microscopy confirmed co-localization of CRT-expressing tumor cells with macrophages. Furthermore, PTT down-regulated ECM components at transcriptional and protein levels, which correlated with increased macrophage infiltration into tumors. CONCLUSIONS: PTT synergizes with CD47 blockade primarily by inducing CRT-dependent pro-phagocytic signaling to provide the "eat me" signal. In parallel, PTT downregulates ECM components, enabling the essential "come near me" process that facilitates macrophage infiltration into tumors. This dual approach significantly improves the macrophage based anti-tumor efficacy of CD47 blockade.
Editorial Expression of Concern: Retinoic acid elicits cytostatic, cytotoxic and immunomodulatory effects on uveal melanoma cells.
Vertuani S, Dubrovska E, Levitsky V … +3 more , Jager MJ, Kiessling R, Levitskaya J
Cancer Immunol Immunother · 2026 Jan · PMID 41603976 · Full text
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Circulating sPD-L1 as a tumor microenvironment-derived biomarker: enhancing diagnostic discrimination accuracy in breast cancer.
Zhang Y, Chen S, Ma J … +2 more , Sun X, Zhou X
Cancer Immunol Immunother · 2026 Jan · PMID 41603965 · Full text
Programmed cell death ligand 1 (PD-L1) plays a pivotal role in breast cancer immune evasion, yet tissue-based detection suffers from invasiveness and spatial heterogeneity. This study investigated circulating soluble PD-...
Programmed cell death ligand 1 (PD-L1) plays a pivotal role in breast cancer immune evasion, yet tissue-based detection suffers from invasiveness and spatial heterogeneity. This study investigated circulating soluble PD-L1 (sPD-L1) as a non-invasive alternative for tumor microenvironment (TME) assessment and breast cancer diagnosis. Serum sPD-L1 levels were evaluated in healthy and breast-affected populations, with correlations assessed against inflammatory markers and clinicopathological parameters. Diagnostic performance of sPD-L1 was compared to conventional biomarkers using receiver operating characteristic (ROC) curve analysis. Cellular-level interactions were investigated by quantifying sPD-L1 and interleukin-6 (IL-6) in culture supernatants. Circulating sPD-L1 expression was significantly elevated in breast cancer versus healthy controls and benign cases, with notably higher levels observed in advanced stages and distant-metastatic cases. Moderate correlations were observed between serum sPD-L1 and various inflammatory indicators. Specifically, ROC curve analysis identified an optimal diagnostic cut-off value of 1.144 ng/mL for sPD-L1, with its discriminative power outperforming conventional biomarkers such as CEA and CA15-3. In vitro, peripheral blood mononuclear cells (PBMCs) co-cultured with breast cancer cells showed enhanced sPD-L1 and IL-6 secretion versus normal epithelial cell co-cultures, with parallel sPD-L1/IL-6 elevation. This coordinated induction was clinically validated by a positive serum sPD-L1/IL-6 correlation. In conclusion, circulating sPD-L1 represents a promising non-invasive biomarker reflecting TME and disease progression, supporting its potential utility for breast cancer diagnostic discrimination.
Adjuvant cytokine-induced killer cell immunotherapy in hepatocellular carcinoma: real-world data and 9-year extended follow-up of a randomized controlled trial.
Shin H, Park Y, Song BG … +14 more , Choi WM, Han HJ, Lee Y, Song TJ, Yeon JE, Lim YS, Hur MH, Lee YB, Cho EJ, Yu SJ, Kim YJ, Lee JH, Yoon JH, Lee JH
Cancer Immunol Immunother · 2026 Jan · PMID 41591582 · Full text
BACKGROUND: Most adjuvant therapies for hepatocellular carcinoma (HCC) have failed except for autologous cytokine-induced killer (CIK) therapy, which prolonged recurrence-free survival (RFS) in a previously reported rand...
BACKGROUND: Most adjuvant therapies for hepatocellular carcinoma (HCC) have failed except for autologous cytokine-induced killer (CIK) therapy, which prolonged recurrence-free survival (RFS) in a previously reported randomized controlled trial (RCT) and real-world data (RWD). METHODS: This study aimed to assess the long-term outcomes of adjuvant CIK therapy using both an extended follow-up of the original RCT and a retrospective cohort study. An extended follow-up analysis of the RCT included 226 patients (114 in the CIK group and 112 in the control group). The follow-up duration was extended from 2 to 9 years after the enrollment of the last patient. In parallel, a retrospective RWD study was performed involving 577 patients from two tertiary centers in Korea, including 251 who received adjuvant CIK therapy and 326 controls. Propensity score matching (PSM) was applied to adjust for baseline imbalances. The primary endpoint was RFS in both studies. RESULTS: In the RWD study (median follow-up = 57.2 months), the CIK group demonstrated significantly prolonged RFS than controls both before PSM (median = 101.2 versus 64.7 months; HR = 0.69, 95% CI 0.53-0.90, P = 0.006) and after PSM (median = 101.2 vs. 65.7 months; HR = 0.64, 95% CI 0.45-0.91, P = 0.01). In the extended follow-up of the RCT (median follow-up = 116.1 months), the CIK group exhibited significantly prolonged RFS (median = 44.0 vs. 30.0 months; hazard ratio [HR] = 0.72, 95% confidence interval [CI] 0.54-0.97, P = 0.033) compared to the control group. CONCLUSIONS: Adjuvant CIK cell therapy significantly improved RFS in both a RWD study and a 9-year extended RCT follow-up, supporting its reproducible benefit in reducing recurrence after curative treatment of HCC. These consistent findings provide strong evidence for the clinical utility of CIK therapy as a durable adjuvant immunotherapeutic strategy for HCC.
Complement contributes to ICI-triggered sialadenitis and predicts ICI efficacy.
Guan X, Liu M, Li A
Cancer Immunol Immunother · 2026 Jan · PMID 41591573 · Full text
While highly efficacious for numerous cancers, immune checkpoint inhibitors (ICIs) can cause unpredictable and potential immune-related adverse events (irAEs). In this study, we aimed to unveil the underlying mechanisms...
While highly efficacious for numerous cancers, immune checkpoint inhibitors (ICIs) can cause unpredictable and potential immune-related adverse events (irAEs). In this study, we aimed to unveil the underlying mechanisms for sialadenitis irAEs under cancer context and assess the response-associated biomarkers for ICI therapy. We found that cholangiocarcinoma patients receiving anti-PD-1 agent showed dry symptoms, and a declined level of serum complement and immune compound were also observed when compared to those without anti-PD-1 treatment. We further demonstrated that the elevated complement activation caused initial salivary gland damage through complement-dependent cytotoxicity after anti-PD-1 administration, which subsequently led to glandular lymphocyte infiltration and dysfunction. We then determined that complement pathway blockade effectively reverse sialadenitis and dysfunction, while anti-PD-1 administration in vivo. Moreover, we determined that sialadenitis irAEs was associated with improved survival rate and ICI response in cholangiocarcinoma. Our findings provided a distinct mechanism showing the occurrence of sialadenitis during ICI treatment, which may explore available biomarkers for ICI efficacy and provide basis for improving ICI application in malignancies.
Portrayed the development of activated T cell to exhausted T cell based on the ratio of CD28 to CTLA4.
Wang Y, Mei X, Zhong J … +5 more , Wang J, Cao J, Zheng S, Qi D, Wang Z
Cancer Immunol Immunother · 2026 Jan · PMID 41591572 · Full text
T cell exhaustion, to some extent, limits the clearance of viruses and tumor cells and accounts for the poor effectiveness of immune therapy. The generally accepted classification of exhausted T cells assigns them as pro...
T cell exhaustion, to some extent, limits the clearance of viruses and tumor cells and accounts for the poor effectiveness of immune therapy. The generally accepted classification of exhausted T cells assigns them as progenitor and terminal statuses. However, the outcome of immune therapy benefits little from this classification. In this study, we constructed a new indicator with the ratio of CD28 to CTLA4 (ccRatio) to continuously characterize the development of T cell from activation to exhaustion. We showed that the ccRatio decreased as T cell exhaustion progressed. We also found that patients who benefitted from anti-CTLA4 treatment had a higher ccRatio value. In addition, by studying the genes that correlated with ccRatio, we found ccRatio is associated with T cell functions which is further confirmed in validation datasets. Furthermore, we found that transcription factor VDR can contribute to differentiation of T cell from activation to exhaustion. The establishment of ccRatio allows us to study T cell exhaustion in a continuous developmental perspective, which is conducive to understand the T cell differentiation and helped in improving existing immunotherapy methods.
Single-cell sequencing and network pharmacology coupled with molecular docking and experimental validation reveal the effects of YPFS on macrophages in stage I non-small cell lung cancer.
Li H, Zhao Q, Yang L … +5 more , Wang L, Ye F, Yang L, Zhang P, Zhang Y
Cancer Immunol Immunother · 2026 Jan · PMID 41591571 · Full text
BACKGROUND: Non-small cell lung cancer (NSCLC), the most common subtype of lung cancer, presents major clinical challenges owing to its highly complex tumor microenvironment and substantial cellular heterogeneity. A comp...
BACKGROUND: Non-small cell lung cancer (NSCLC), the most common subtype of lung cancer, presents major clinical challenges owing to its highly complex tumor microenvironment and substantial cellular heterogeneity. A comprehensive understanding of the immune landscape-particularly the phenotypic diversity and functional roles of macrophage subpopulations-is critical for identifying novel therapeutic targets and developing more effective treatment strategies. METHODS: We constructed a comprehensive single-cell atlas of Stage I NSCLC using single-cell RNA sequencing (scRNA-seq) to characterize immune heterogeneity, with particular emphasis on macrophage subsets. Network pharmacology was employed to investigate the interactions between AHSA1 and bioactive compounds derived from the traditional Chinese medicine formulation Yu Ping Feng San (YPFS). To further evaluate these interactions, molecular docking simulations were performed to assess binding affinities and elucidate the potential regulatory effects on macrophage polarization. RESULTS: ScRNA-seq analysis revealed heterogeneous macrophage subtypes, each exhibiting distinct roles in tumor progression. AHSA1 was identified as a key regulator of macrophage polarization, with higher expression levels associated with unfavorable prognosis. Through network pharmacology and molecular docking, strong binding affinities were observed between AHSA1 and Yu Ping Feng San (YPFS)-derived compounds, including wogonin, kaempferol, and quercetin. Notably, quercetin displayed the highest binding affinity and exerted the strongest inhibitory effect on M2 macrophage polarization. CONCLUSION: These findings identify AHSA1 as a pivotal regulator of macrophage polarization in NSCLC and position quercetin as a promising macrophage-targeted therapeutic candidate. Furthermore, the results highlight the potential of Yu Ping Feng San (YPFS) as a complementary therapeutic strategy for NSCLC, offering a bridge between traditional Chinese medicine and modern oncology.
Non-thyroidal illness syndrome predicts poor prognosis in hepatocellular carcinoma patients treated with atezolizumab and bevacizumab.
Chen IW, Lin CW, Lin PT … +8 more , Teng W, Su CW, Wu TH, Hsieh YC, Chen WT, Lin CC, Lin SM, Lin CY
Cancer Immunol Immunother · 2026 Jan · PMID 41591568 · Full text
BACKGROUND: Atezolizumab plus bevacizumab (Ate/Bev) is the first-line systemic therapy for unresectable hepatocellular carcinoma (HCC). However, the prognostic impact of immune-related thyroid adverse events (irTAEs), pa...
BACKGROUND: Atezolizumab plus bevacizumab (Ate/Bev) is the first-line systemic therapy for unresectable hepatocellular carcinoma (HCC). However, the prognostic impact of immune-related thyroid adverse events (irTAEs), particularly non-thyroidal illness syndrome (NTIS), remains unclear. METHODS: We retrospectively analyzed 70 patients with unresectable HCC treated with Ate/Bev. Thyroid function was monitored at baseline and during the treatment. IrTAEs were classified as NTIS (low T3 and/or free T4 with normal or low TSH levels) or thyroid adverse events (hypothyroidism or thyrotoxicosis). Clinical outcomes, including progression-free survival (PFS) and overall survival (OS), were assessed using Kaplan-Meier and Cox regression analysis. Subgroup analyses were performed to examine the associations between liver function, nutritional status, and HCC etiology. RESULTS: Among 70 patients (median age, 64 years; 80% male), 24 (34.3%) developed irTAEs: 11 had NTIS and 13 had thyroid AEs. NTIS was independently associated with worse OS (adjusted hazard ratio [HR], 2.51; P = 0.041) and shorter median OS (5.4 months). In contrast, thyroid AEs were associated with a favorable trend in PFS (adjusted HR, 0.37; P = 0.073) and a higher objective response rate (53.8% vs. 9.1%; P = 0.006). NTIS was correlated with deterioration in albumin level, body mass index, and ALBI grade. Viral HCC was associated with fewer thyroid AEs, while alcohol-related HCC trended toward NTIS. CONCLUSIONS: Thyroid dysfunction during Ate/Bev therapy is prognostically significant. NTIS reflects systemic deterioration and portends poor survival, whereas thyroid AEs may suggest favorable immune activation. Routine monitoring of thyroid function may aid in risk stratification.
Prediction of tumor-infiltrating lymphocytes through habitat radiomics and exploration of response mechanisms in neoadjuvant immunochemotherapy-treated lung cancer.
Geng Z, Hu Y, Zhou S … +8 more , Wu G, Gong Z, Feng R, Huang Z, Mei P, Li K, Ye G, Liao Y
Cancer Immunol Immunother · 2026 Jan · PMID 41591567 · Full text
BACKGROUND: Neoadjuvant immunochemotherapy (NAIC) induces tumor microenvironment remodeling in non-small cell lung cancer (NSCLC), presenting challenges for treatment response assessment. This study developed and validat...
BACKGROUND: Neoadjuvant immunochemotherapy (NAIC) induces tumor microenvironment remodeling in non-small cell lung cancer (NSCLC), presenting challenges for treatment response assessment. This study developed and validated a habitat radiomics approach for non-invasive prediction of tumor-infiltrating lymphocyte (TIL) status to evaluate NAIC response in NSCLC. METHODS: This retrospective study enrolled 238 NSCLC patients following NAIC for clinical analysis, of which 201 patients met criteria for radiomics analysis. Patients were classified into TIL-positive and TIL-negative groups based on pathological assessment. Post-treatment computed tomography (CT) images were analyzed using K-means clustering to identify tumor habitat sub-regions for radiomic feature extraction. Seven machine learning algorithms were evaluated for TIL status prediction. Model interpretability was assessed through SHapley Additive exPlanations (SHAP) analysis. Single-cell RNA sequencing (scRNA-seq) data were analyzed to compare major pathological response (MPR) and non-MPR tumor microenvironments through cell type annotation, differentiation trajectory analysis, and intercellular communication network analysis. RESULTS: Pre-treatment neutrophil-to-lymphocyte ratio (NLR) showed association with pathological response in multivariable analysis. The radiomics cohort was randomly divided 7:3 into training (n = 140) and test (n = 61) sets. The Random Forest model achieved an area under the receiver operating characteristic curve (AUC) of 0.823 (95% CI: 0.694-0.932) in the test set, and the habitat radiomics model stratified patients into high and low recurrence risk groups. Single-cell analysis identified immunosuppressive features in non-responding tumors, characterized by expansion of SERPINB9 + regulatory T cells (Tregs) that regulated suppressive intercellular communication networks. CONCLUSIONS: This study establishes a habitat radiomics model for non-invasive assessment of TIL status following neoadjuvant immunochemotherapy in NSCLC. The model shows reliable predictive performance and prognostic stratification capability, offering potential clinical utility for treatment response evaluation and patient selection.
First-line PD-1 blockades combined with TKIs for metastatic non-clear cell renal cell carcinoma: a real-world multicenter retrospective study.
Zhong X, Huang T, Peng Y … +9 more , Jing T, Ng C, Liu X, Wei W, Zhang Z, Han H, Chen M, Huang J, Dong P
Cancer Immunol Immunother · 2026 Jan · PMID 41591551 · Full text
BACKGROUND: Metastatic non-clear cell renal cell carcinoma (mnccRCC) are several rare subtypes of renal cell carcinoma, with standard treatment under investigation. This study retrospectively analyzes the largest Chinese...
BACKGROUND: Metastatic non-clear cell renal cell carcinoma (mnccRCC) are several rare subtypes of renal cell carcinoma, with standard treatment under investigation. This study retrospectively analyzes the largest Chinese cohort to assess the efficacy and safety of PD-1 blockades combined with tyrosine kinase inhibitors (TKIs) in mnccRCC. PATIENTS AND METHODS: A retrospective review was conducted on treatment-naive patients with mnccRCC who received first-line PD-1 blockades combined with TKIs or TKIs monotherapy. The baseline characteristics of the patients and adverse events (AEs) were collected. Efficacy measures included objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). RESULTS: The study enrolled 183 patients (99 TKI monotherapy, 84 combination therapy), with a median follow-up time of 20.0 (IQR, 11.1-32.4) months. ORR (32.1% vs. 20.2%) and DCR (82.1% vs. 55.6%) were improved in combination group compared with TKI group. Patients receiving combination therapy had a longer PFS and OS compared with those receiving TKI monotherapy [median PFS (95% CI): 19.1 (11.1-27.5) vs 8.1 (6.2-10.2)m, P < 0.001; median OS: not reached vs 44.1 (95% CI 27.4-70.0)m P = 0.017]. Subgroup analyses identified good performance status, non-chromophobe/Mit family translocation histologies and intermediate/poor IMDC classification derived pronounced survival advantages. The incidence of treatment-related AEs of grade three or higher was similar between the two groups (35.7% vs. 27.3%). CONCLUSIONS: PD-1 blockades combined with TKIs appeared an effective and safe choice in first-line treatment of mnccRCC, especially in individuals with good performance status, non-chromophobe/Mit family translocation histologies, and intermediate/poor IMDC classification.
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