Current evidence demonstrates the efficacy of anti-programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICIs) in patients with recurrent or metastatic head and neck squamous cell carcinoma (RMHNSCC), but only a limited number of patients can benefit. TP53 alteration is one of the most frequent genetic events in HNSCC and may be reflected by aberrant p53 protein expression in tumor cells. Nevertheless, the association between p53 immunohistochemical expression and clinical outcomes in RMHNSCC patients receiving anti-PD-1 therapy remains unclear. We retrospectively analyzed 141 patients with recurrent or metastatic HNSCC who received anti-PD-1 ICIs between January 2017 and December 2023. Immunohistochemical staining in the pretreatment tumor was used to evaluate the expression of p53 and was correlated with the treatment outcome of anti-PD-1 ICIs. Positive p53 expression and tumor proportion score (TPS) <50% were significantly correlated with a poor response to anti-PD-1 ICIs. The overall response rates were 31% and 11% in patients with negative and positive p53 expressions, respectively (P=0.008). Univariate survival analysis showed that positive p53 expression (P=0.012) and TPS <50% (P=0.035) were significantly associated with worse progression-free survival (PFS), and positive p53 expression (P<0.001) was significantly correlated with inferior overall survival (OS). Multivariate analysis revealed that positive p53 expression was an independent poor prognosticator for worse PFS and inferior OS. The 2-year PFS and OS rates were 16% and 32% in patients with negative p53 expression and 8% and 10% in patients with positive p53 expression, respectively. In conclusion, p53 expression in pretreatment tumor specimens was associated with response and survival outcomes in patients with RMHNSCC receiving anti-PD-1 ICIs. Positive p53 expression may serve as a potential prognostic marker for inferior clinical outcomes in this population. Further prospective studies incorporating TP53 sequencing and immune microenvironmental profiling are warranted to validate its clinical utility.

To evaluate real-world survival outcomes of consolidation immunotherapy after concurrent chemoradiotherapy (cCRT) in patients with unresectable stage III non-small cell lung cancer (NSCLC) treated at a tertiary cancer center in Lebanon. This is a retrospective cohort study that included patients with unresectable stage III NSCLC treated between 2019 and 2025 with definitive cCRT, with or without ICIs (durvalumab or atezolizumab). The primary endpoint was progression-free survival (PFS), analyzed using Kaplan-Meier and Cox regression methods, adjusting for variables, including PD-L1 status. Among 92 eligible patients, 52 (56.5%) received consolidation immunotherapy, and 40 (43.5%) received cCRT alone. Median follow-up was 22.3 months. Median PFS was 19.0 months (95% CI: 12.8-25.2) with ICIs versus 10.0 months (95% CI: 7.0-13.1) without (log-rank P=0.210). On multivariable Cox analysis, immunotherapy was associated with a favorable trend toward improved PFS (HR=0.53, 95% CI: 0.26-1.11; P=0.09). PD-L1 positivity independently predicted longer PFS (HR=0.42, 95% CI: 0.21-0.84; P=0.014), while high tumor grade predicted inferior outcomes (HR=1.89, 95% CI: 1.04-3.43; P=0.038). Immunotherapy after cCRT was associated with numerically and clinically meaningful improvement in PFS, consistent with the landmark PACIFIC trial. PD-L1 expression emerged as an independent prognostic and predictive biomarker, supporting biomarker-driven treatment strategies. These findings validate the clinical benefit of ICIs in a Middle Eastern low- and middle-income setting, reinforcing the importance of equitable access to immunotherapy.

Neoadjuvant immunotherapy (NAIC) is feasible and associated with a high rate of pathologic complete response (pCR) in deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) gastric and gastroesophageal junction cancers (GC/GEJC). However, the association between NAIC efficacy and pathologic characteristics remains unclear. We conducted a retrospective study to evaluate this relationship. Patients with dMMR/MSI-H GC/GEJC who received neoadjuvant immunotherapy were included. The effects of different neoadjuvant regimens were compared, and pathologic characteristics were analyzed between tumor regression grade TRG1 and TRG2 groups. The χ2 test was used to estimate relative risks (RRs) with 95% CIs. In total, 39 patients with dMMR/MSI-H GC/GEJC who received neoadjuvant immunotherapy were included. All patients underwent complete R0 resection; 22 patients (56%) achieved pCR in both the primary tumor and lymph nodes. The chemotherapy plus immunotherapy group and the immunotherapy-only group achieved significantly higher TRG1 rates compared with the chemotherapy group (RR=4.2, 95% CI=1.5-15.0, P=0.0004; and RR=4.4, 95% CI=1.7-15.7, P=0.003, respectively). The intestinal subtype also demonstrated a higher TRG1 rate than the mixed subtype (RR=2.5, 95% CI=1.1-8.7, P=0.0196). Neoadjuvant immunotherapy achieved a high pCR rate in patients with dMMR/MSI-H locally advanced, resectable GC/GEJC relative to chemotherapy. The intestinal subtype may serve as a histologic biomarker of enhanced sensitivity to neoadjuvant immunotherapy in this patient population.

Dimethyl fumarate (DMF) exerts cytoprotective effects via antioxidant pathway activation. Whether it modulates antitumor immunity through novel cell death forms remains unclear. GSH/GSSG levels were measured in HCC and adjacent tissues using assay kits, with FDX1 and GCLM expression detected by IHC. Cuproptosis-related proteins (NRF2, FDX1, LIAS) and DLAT oligomerization were assessed by western blotting and immunofluorescence in HCC cells. Intracellular GSH, glutamate, Cu2+, and γ-GCS activity were measured biochemically. Cell viability was determined by CCK-8. CD8+ T cells cocultured with HCC cells were analyzed for GZMB, IFN-γ, and TNF-α by flow cytometry; cytotoxicity was evaluated by LDH release. HCC tissues exhibited elevated GSH, downregulated FDX1, and upregulated GCLM compared with adjacent tissues. Elesclomol-Cu2+ (ES-Cu) induced cuproptosis, upregulating NRF2, downregulating FDX1 and LIAS, promoting DLAT oligomerization, and causing GSH depletion and Cu2+ accumulation; GSH-MEE reversed these effects. DMF inhibited GSH metabolism, evidenced by NRF2 downregulation, decreased GSH, increased GSSG, and suppressed γ-GCS activity. Mechanistically, DMF promoted cuproptosis via NRF2 inhibition, which was reversed by NRF2 overexpression. DMF-induced cuproptosis enhanced TNF-α, IFN-γ, and GZMB expression and increased CD8+ T-cell cytotoxicity; the copper chelator tetrathiomolybdate blocked these effects. DMF induces cuproptosis by modulating GSH metabolism, thereby activating CD8+ T-cell-mediated anti-HCC immunity. This offers potential targets for novel combination therapeutic strategies.

To explore the clinical characteristics of sintilimab-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and provide references for prevention, diagnosis, and treatment. Clinical reports of sintilimab-induced SJS/TEN published before March 31st, 2026 were collected by searching the database, and clinical data were extracted for retrospective analysis. Twenty-three men (69.7%) and ten women (30.3%) were included, with a median age of 66 years (range: 27, 82). The median time for the appearance of SJS/TEN was 20 days (range: 2, 240), and the median cycle was 1 cycle (range: 1, 17). Among these 33 patients, 72.7% were diagnosed with TEN, 15.2% with SJS, and 12.1% with SJS/TEN overlap. The main clinical symptoms were rash (75.0%), erosion (82.1%), bullae/blisters (78.6%), erythema (67.9%), epidermal detachment (57.1%), and pruritus (50.0%), high fever (46.4%), and ocular symptoms (35.7%). Furthermore, 57.6% of the patients experienced mucosal lesions, mainly affecting the mouth (89.5%), genitalia (57.9%), and conjunctiva (52.6%). Skin biopsy showed poptotic keratinocytes (83.3%), subepidermal blisters (50.0%), and inflammatory cell infiltration (100%). After discontinuing sintilimab and receiving systemic steroids and intravenous immunoglobulins (IVIG) treatment, 87.9% of the patients experienced improvement in skin symptoms, while 12.1% of the patients died from TEN. SJS/TEN is a rare and life-threatening cutaneous adverse reaction of sintilimab. During the use of sintilimab, clinicians should be aware of the possibility of SJS/TEN, especially within the first month. For patients diagnosed with SJS/TEN, sintilimab should be discontinued, and they should receive systemic steroids and IVIG treatment.

Acute myeloid leukemia (AML) is a hematological malignancy associated with poor prognosis. Recent developments in natural killer (NK) cell-based immunotherapies have resulted in the robust expansion of NK cells with enhanced cytotoxicity against hematological malignancies. However, disease relapse remains a challenge. Another therapeutic intervention that has garnered high interest is the use of lysine-specific demethylase 1 (LSD1) inhibitors for AML treatment. Here, we investigated whether LSD1 inhibition could synergize with ex vivo expanded NK (exNK) cells in a primary AML sample. Interestingly, we observed that treatment with the LSD1 inhibitors, bomedemstat and GSK-LSD1, led to the upregulation of multiple stress ligands known to activate NK cells. Importantly, this increased stress ligand expression was associated with enhanced NK cell-mediated cytotoxicity, suggesting the potential for both therapies to be used synergistically. To our knowledge, this is the first study to assess the combination of LSD1 inhibition and exNK cells in AML.

Oral squamous cell carcinoma (OSCC) is frequently refractory to immune checkpoint blockade, in part because the tumor microenvironment is enriched with immunosuppressive, M2-like tumor-associated macrophages. Auranofin (ARN), an FDA-approved thioredoxin reductase inhibitor, induces oxidative and proteotoxic stress and may remodel myeloid compartments to improve immunotherapy responsiveness. Here, we investigated whether ARN sensitizes OSCC to PD-1 blockade through DUSP1-associated macrophage reprogramming. Using an immunotherapy-resistant, syngeneic MOC2 murine OSCC model, mice bearing established tumors were treated with vehicle, ARN, anti-PD-1, or combination therapy. Combination treatment significantly improved survival and produced the most pronounced reduction in tumor burden compared with control and monotherapy groups. In vitro, ARN increased Dusp1 mRNA in bone marrow-derived macrophages polarized toward an M2 phenotype in a time- and dose-dependent manner. In vivo, RNAscope analysis demonstrated increased Dusp1 expression within tumors following ARN and/or anti-PD-1, with co-localization patterns consistent with a shift toward a pro-inflammatory macrophage state. Functionally, ARN directly promoted macrophage repolarization, increasing the M1/M2 ratio by flow cytometry and suppressing expression of the M2 marker arginase-1 (Arg1). In tumors, ARN and anti-PD-1 each increased the frequency of M1-like macrophages while reducing M2-like populations. Adaptive immune profiling further showed increased CD8[+] T-cell infiltration across treatments, peaking in the combination group. Tumor cells also upregulated PD-L1, PD-L2, and CTLA-4, consistent with heightened immune stress. Collectively, these findings support repurposing ARN as an immunomodulatory adjuvant to overcome resistance to PD-1 blockade in OSCC by inducing DUSP1-linked macrophage remodeling and enhancing cytotoxic T-cell-associated antitumor immunity.

Glioblastoma (GBM) is the most lethal primary brain tumor, with a median survival of 15 months despite intensive treatment. Chimeric antigen receptor (CAR) T-cell therapy, while transformative in hematological malignancies, consistently fails in GBM because the immunosuppressive tumor microenvironment (TME) drives T-cell exhaustion. We examined transcriptional programs, microenvironmental factors, and metabolic competition that collectively drive exhaustion in this context. Then we reviewed 5 convergent engineering strategies: localized cytokine delivery to bypass autocrine deficits; adjunctive antibody therapies to remodel the TME; oncolytic viruses armed with chemoattractants or cytokines as immunomodulators; coexpression of cytokine or chemokine receptors to provide survival signals; and multiplexed CRISPR-Cas9 editing to disrupt exhaustion checkpoints and enable site-specific CAR integration. Locoregional delivery consistently outperforms systemic administration, demonstrating that physical barriers are as critical as cellular engineering. Despite this progress, antigen heterogeneity, metabolic limitations, and the need for combinatorial targeting remain the principal unresolved challenges. An overview of the key concepts discussed in this review is presented in the graphical abstract.

Immune checkpoint inhibitor therapy has become increasingly recognized as a trigger for hemophagocytic lymphohistiocytosis, a life-threatening hyperinflammatory syndrome that may lead to organ failure without timely interventions. Given the rarity of this entity, patients are often misdiagnosed with more common oncologic complications. In the present series, we describe 3 patients with diverse clinical pictures evaluated at hospital admissions, who were ultimately diagnosed with immune checkpoint inhibitor-associated hemophagocytic lymphohistiocytosis. Treatment consisted of dexamethasone combined with an immunosuppressive agent such as anakinra, ruxolitinib, or tocilizumab, with variable clinical responses among patients. These cases highlight the importance of maintaining a high index of suspicion for hemophagocytic lymphohistiocytosis in patients presenting with systemic inflammation during immune checkpoint inhibitor therapy.

Colorectal cancer (CRC) is a prevalent malignancy worldwide, with its immune evasion representing a pivotal barrier to effective immunotherapy. OLR1 is abnormally expressed in a variety of cancers, but its function in the CRC immune microenvironment and the upstream and downstream modulatory mechanisms remain unclear. Based on the TCGA-COAD data set, OLR1 was upregulated in colorectal cancer (CRC) and correlated with CD8 + T-cell infiltration. Functional assays (qRT-PCR, Western blotting, LDH, ELISA, CCK-8, CFSE, colony formation, Transwell, and flow cytometry) confirmed that OLR1 suppressed CD8 + T-cell function and promoted tumor malignancy. GSEA and inhibitor-based functional validation identified key pathways downstream of OLR1. Mechanistically, bioinformatics, RIP, RNA pull-down, MeRIP, and actinomycin D assays revealed that IGF2BP3 stabilized OLR1 mRNA. Rescue experiments further demonstrated that the IGF2BP3/OLR1 axis regulated the aforementioned pathways and CRC immune evasion. OLR1 was upregulated in CRC and negatively associated with CD8 + T-cell infiltration. Knockdown of OLR1 significantly enhanced the antitumor function of CD8 + T cells. Mechanistically, IGF2BP3 stabilized OLR1 mRNA and up-regulated its expression in an m6A modification-dependent manner, thereby activating the PI3K/AKT/mTOR pathway to inhibit the antitumor activity of CD8 + T cells. IGF2BP3 stabilized OLR1 through m6A modification and activated the PI3K/AKT/mTOR pathway, thereby repressing the antitumor activity of CD8 + T cells and promoting immune evasion in CRC.

Immune checkpoint inhibitors (ICI) have revolutionized the treatment of melanoma and renal cell carcinoma (RCC). Immune therapy response outcomes are based on radiographic measurements of cancer sites alone, without considering whether these sites contain a viable tumor that has metastatic potential. We hypothesized that ICI may lead to residual radiographic abnormalities that either contain nonviable tumor or tumor without metastatic potential that could be controlled with local therapy. In this retrospective cohort study, we identified 8 patients with melanoma and 4 with RCC who had an operable residual metastasis after major tumor response to ICI treatment. On the basis of histologic analysis, 10 (83.3%) of the resected samples showed viable tumor while 2 (16.7%) showed no viable tumor cells on pathology. After surgical removal (11), or radiosurgery (1), to the lesion, all patients had no evidence of melanoma or RCC recurrence for the duration of follow-up. Time from definitive treatment to last follow-up was a mean of 5.9 years (1.1-11.9 y). ICI therapy in melanoma and RCC may lead to a response where existing lesions or new lesions either have no viable cancer or lose their metastatic capacity. Surgical removal or local radiation to those lesions with residual cancer can render patients' long-term disease-free without the need for additional systemic therapy. Consideration of local therapy approaches in patients with isolated residual metastatic disease after ICI response is clinically justified.

Immune checkpoint inhibitors (ICIs) have significantly improved outcomes across multiple malignancies but are associated with immune-related adverse events, including colitis. Although generally uncommon, ICI-induced colitis can lead to significant morbidity and treatment interruption, and data on its incidence and risk factors in the Middle East remain limited. We conducted a retrospective study of adult cancer patients treated with ICIs at a tertiary care center between December 2018 and March 2023. Clinical and treatment-related variables were collected, and univariable and multivariable logistic regression analyses were performed to identify predictors of colitis. Among 784 patients, 19 (2.4%) developed ICI-related colitis. Most cases were moderate to severe, and 57.9% required hospitalization, with a median length of stay of 7 days. All patients had advanced disease. Endoscopic evaluation, performed in 42.1% of patients, demonstrated heterogeneous disease distribution. ICI therapy was discontinued in 78.9% of patients and resumed in 36.8%. Corticosteroids were administered in 68.4% of patients, with a response rate of 92.3%; 1 patient required infliximab. One colitis-related death occurred. In univariable analysis, autoimmune disease, CTLA-4 inhibitor exposure, combination immunotherapy, and concurrent targeted therapy were significantly associated with colitis. In multivariable analysis, autoimmune disease (OR =6.10, 95% CI: 1.55-24.08; P =0.010), combination immunotherapy (OR =3.56, 95% CI: 1.09-11.63; P =0.035), and concurrent targeted therapy (OR =3.88, 95% CI: 1.31-11.54; P =0.015) remained independent predictors. ICI-induced colitis is an uncommon but clinically meaningful toxicity, and recognizing patients at higher risk may help guide closer monitoring and improve clinical management.

Photosensitizer-based antibody conjugates can provide tumor-selective phototoxicity by combining receptor-mediated targeting with local light activation. IR700-based near-infrared photoimmunotherapy represents the clinical benchmark for this strategy; however, photosensitizers with alternative cellular trafficking and phototoxic mechanisms remain of interest. We developed and characterized 2 cetuximab-I21 conjugates, cetuximab-I21-2 and cetuximab-I21-3, targeting epidermal growth factor receptor (EGFR)-expressing tumors. The chemical structures and key photophysical properties of the I21 payload-linkers are disclosed in this revision. Both conjugates achieved a drug-to-antibody ratio of 8 and demonstrated strictly light-dependent cytotoxicity in EGFR-positive cells, with IC 50 values of 0.051-1.093 μg/mL in A431 cells and no detectable dark toxicity. EGFR-low cells showed >400-fold reduced sensitivity, supporting receptor-dependent selectivity. Mechanistic studies revealed receptor-mediated internalization and endolysosomal trafficking, with peak lysosomal colocalization at 3 hours (Pearson r =0.81), followed by mitochondrial membrane depolarization and dose-dependent apoptosis-associated cell death. In vivo fluorescence imaging demonstrated tumor-selective accumulation with sustained retention through 96 hours. In A431 xenografts, cetuximab-I21-3 with triple irradiation (200 J/cm 2 ×3) achieved 50.42% tumor growth inhibition (P =0.0002). These findings establish cetuximab-I21 as a light-activated, EGFR-targeted antibody-photosensitizer conjugate with a mechanism distinct from that of canonical IR700-based NIR-PIT. Direct IR700 comparison, immune activation studies, photosafety evaluation, and light-dose optimization will be required to define its translational potential.

To investigate the clinical profile of nivolumab-induced autoimmune hemolytic anemia (AIHA) and to reveal the diagnostic and therapeutic patterns of this disease. Articles on nivolumab-induced AIHA published before October 31, 2025 were included. Clinical data were collected for retrospective analysis. A total of 29 patients were included, with a median age of 67 years (range: 18, 89). AIHA occurred at a median of 57 days (range: 6, 390) following initial nivolumab administration, with a median treatment cycle of 3 cycles (range: 1, 39). Fatigue (76.9%) and dyspnea (53.8%) were the predominant clinical manifestations. The laboratory analysis indicated that the median concentrations of hemoglobin and lactate dehydrogenase were 6.2 g/dL (range: 3.5, 8.7) and 710.5 U/L (range: 200, 1574), respectively. Direct antiglobulin test (DAT) results were seronegative in 10.3% and seropositive in 89.7%. Following nivolumab discontinuation and administration of systemic steroids, immunosuppressants, and transfusion support, 89.7% of patients achieved remission. AIHA is a rare and fatal event of nivolumab. DAT may yield negative results in some cases. Warm AIHA is the most common type of nivolumab-induced AIHA. Systemic steroids are the first-line option for AIHA. Refractory AIHA and cAIHA require additional immunosuppressive therapy.