Claspin (CLSPN), previously identified as a cisplatin-resistance driver and immunotherapy target in urothelial carcinoma, has not been characterized in pancreatic cancer, which remains poorly responsive to immune checkpoint blockade. This study aimed to determine whether CLSPN can be a target for immunotherapy in pancreatic cancer.

CLSPN expression and its prognostic association were analyzed using a TCGA pancreatic adenocarcinoma cohort. CLSPN induction by cisplatin (CDDP) and oxaliplatin (L-OHP) was assessed by western blotting and quantitative RT-PCR. The antigen-specific reactivity of previously established CLSPN-specific, HLA-A*02:01-restricted TCR-T cells (clone yc3) against the pancreatic cancer cell line PANC-1 was evaluated by IFN-γ ELISPOT assay, with and without platinum pretreatment.

High CLSPN expression was associated with shorter overall, disease-free, disease-specific, and progression-free survival. CLSPN protein and mRNA expression were detected in pancreatic cancer cell lines. The expression of CLSPN was increased by platinum exposure. yc3 TCR-T cells specifically recognized CLSPN peptide-pulsed T2 cells and produced IFN-γ upon coculture with HLA-A*02:01⁺/CLSPN⁺ PANC-1 cells, and their reactivity was increased by platinum treatment.

CLSPN is a platinum-inducible immunotherapy target in pancreatic cancer, and combining CLSPN-specific TCR-T cell therapy with platinum-based chemotherapy is a promising strategy for this disease.

Immune checkpoint inhibitors are effective treatments for a variety of malignancies. However, evidence supporting their use in patients with multiple primary cancers remains limited because these patients are typically excluded from clinical trials.

We report the case of a 68-year-old man with synchronous squamous cell carcinomas of the esophagus and mandibular gingiva, both with a combined positive score of ≥1 and <10. The patient was treated with pembrolizumab in combination with cisplatin and 5-fluorouracil, resulting in a clinical complete response of the gingival and metastatic lesions and near-complete response of the esophageal tumor. Treatment was well-tolerated, and the patient regained oral intake and body weight.

The mechanisms underlying the favorable response remain unclear and may involve factors beyond conventional tumor biomarkers. This case suggests that PD-1 blockade provides a substantial clinical benefit in select patients with multiple primary cancers.

Dermatomyositis is a recognised paraneoplastic inflammatory myopathy although its association with oesophageal malignancy is uncommon. Most reported cases either precede or accompany the initial diagnosis of malignancy. We report a man in his late fifties with previously treated oesophageal squamous cell carcinoma who developed florid dermatomyositis after approximately 6 years of sustained remission following chemotherapy, radiotherapy and pembrolizumab therapy. He presented with progressive proximal muscle weakness, dysphagia and characteristic cutaneous manifestations accompanied by markedly elevated creatine kinase levels. Fluorodeoxyglucose positron emission tomography-CT demonstrated metastatic oesophageal squamous cell carcinoma involving the thoracic oesophagus, abdominal lymph nodes and liver. Corticosteroids followed by paclitaxel-carboplatin rechallenge chemotherapy resulted in marked improvement in both inflammatory manifestations and tumour burden. The chronology was notable for parallel evolution of inflammatory activity and metastatic disease after prolonged oncological remission.

Immune-checkpoint inhibitors (ICIs) plus chemotherapy have demonstrated survival benefits in extensive-stage small cell lung cancer (SCLC). The integration of immunotherapy with concurrent chemoradiotherapy (CCRT) may improve survival outcomes in limited-stage SCLC (LS-SCLC). This phase II randomized controlled study was designed to evaluate the efficacy and safety of toripalimab consolidation versus observation in patients with LS-SCLC after CCRT.

We conducted this phase II, randomized controlled trial in patients with LS-SCLC who had completed CCRT. Eligible patients were randomized 1:1 to either toripalimab consolidation (240 mg every 3 weeks for up to 6 months) or observation. Randomization was stratified according to disease stage (I or II vs III) and the receipt of prophylactic cranial irradiation (PCI) (yes vs no). The primary endpoint was progression-free survival (PFS). The secondary endpoints included overall survival (OS), objective response rate and toxicities.

Between June 30, 2020, and May 31, 2024, a total of 98 patients were randomized to receive either toripalimab consolidation (n=49) or observation (n=49) after CCRT. The trial was prematurely terminated on May 31, 2024. Objective responses were observed in 14 of 23 patients (60.9%) in the toripalimab group and in 9 of 24 patients (37.5%) in the observation group. The median PFS was not reached in the toripalimab group, compared with 14.1 months (95% CI 2.8 to 25.4) in the observation group (HR, 0.55; 95% CI 0.31 to 0.96). The median OS was not reached with toripalimab, compared with 30.3 months (95% CI 20.4 to 40.2) with observation (HR, 0.39; 95% CI 0.19 to 0.80). Treatment-related toxicities were generally mild. Adverse events led to discontinuation of study drug in 6 of 48 patients (12.5%) in the toripalimab group. Grade 3 pneumonitis or radiation pneumonitis occurred in two patient (4.2%) in the toripalimab group and one patient (2.0%) in the observation group. No grade 4 or 5 adverse events occurred in either group. Subgroup analyses of PFS and OS favored toripalimab over observation across all predefined subgroups, including age, sex, Eastern Cooperative Oncology Group performance status, smoking status, disease stage, response to CCRT and the receipt of PCI.

Consolidative toripalimab showed promising signals of improved PFS and OS with a manageable safety profile in patients with LS-SCLC. These findings warrant confirmation in larger, adequately powered randomized trials.

Short-chain fatty acids (SCFAs) produced by the gut microbiota are increasingly recognized as regulators of host immunity, yet the role of individual SCFAs in shaping the tumor immune microenvironment in colorectal cancer (CRC) remains poorly defined. This study aims to investigate the role of propionate in antitumor immunity and immunotherapy responsiveness in CRC.

SCFA levels, systemic inflammatory cytokine levels, and immune cell subsets were quantified in peripheral blood and tumor tissues from patients with CRC and healthy controls. Syngeneic microsatellite instability-high (MSI-H) and microsatellite stable (MSS) murine CRC models were used to evaluate the therapeutic efficacy of propionate alone and in combination with anti-programmed death-ligand 1 (PD-L1) blockade. CD8⁺ T-cell infiltration, activation status, and cytotoxic function were assessed by flow cytometry, immunohistochemistry, and single-cell RNA sequencing. Mechanistic investigations included acetylation-dependent protein modification analyses. Molecular analyses of signaling pathways were performed to delineate the regulatory axis underlying propionate-mediated immune modulation.

Propionate levels were inversely associated with systemic inflammation and positively correlated with intratumoral CD8⁺ T-cell infiltration. Propionate supplementation enhanced CD8⁺ T-cell cytotoxicity, promoted CD8⁺ T-cell tumor infiltration and suppressed tumor growth in both MSI-H and MSS mouse models. Notably, propionate significantly potentiated the efficacy of PD-L1 blockade and restored immunotherapy sensitivity in otherwise resistant MSS tumors. Mechanistically, propionate induced acetyl-CoA acetyltransferase 1-dependent acetylation and proteasomal degradation of argininosuccinate synthase 1 (ASS1), resulting in activation of signal transducer and activator of transcription 1 signaling and upregulation of the T cell-recruiting chemokine C-X-C motif chemokine ligand 9. In clinical samples, low ASS1 expression was associated with high CD8⁺ T-cell infiltration.

This study revealed the role of propionate in regulating the tumor immune microenvironment in CRC, suggesting propionate as a promising strategy to overcome immune exclusion and enhance the efficacy of immunotherapy.

Combining immunotherapy with endocrine therapy and/or chemotherapy promotes prognosis in patients with estrogen receptor-positive/HER2-negative (ER⁺HER2^-) breast cancer; however, the unclear underlying mechanisms limit their widespread application in clinical practice. This study aimed to investigate how ER signaling regulates antitumor immunity and influences responses to chemoimmunotherapy.

We evaluated pathological complete response rates between ER-positive and ER-negative breast cancer patients across internal and external cohorts treated with immunotherapy and neoadjuvant chemotherapy. Mechanistic studies were conducted to explore the crosstalk between ER and immunogenic cell death (ICD) through high mobility group box 1 (HMGB1) SUMOylation. The therapeutic potential of chemoimmunotherapy regimens was assessed using immunocompetent mouse models of ER⁺ breast cancer.

Patients with ER^- breast cancer had higher pathological complete response rates after immunotherapy and neoadjuvant chemotherapy compared with those with ER⁺ breast cancer in both internal and external cohorts. Enhanced immune responses were observed in ER^- breast cancer after chemotherapy, which was attributed to the induction of ICD via the release of HMGB1. Mechanistically, ER inhibits HMGB1 release by directly interacting with the HMG Box B domain and suppressing its SUMOylation at the K114 site, thereby suppressing the antitumor immune response.

Therapeutically, combining ER antagonist with chemotherapy potentiated the efficacy of PD-1 blockade through HMGB1 in an immunocompetent mice model. These findings provide new mechanistic insights and clinical strategies for addressing immunotherapy resistance in ER⁺ breast cancer patients.

PTPN22, a protein tyrosine phosphatase (PTP) family member, has recently emerged as an intracellular regulator in adaptive immune cells. However, its function in natural killer (NK) cells remains unclear despite its high expression in innate immune cells.

We analyzed single-cell RNA-sequencing (scRNA-seq) datasets and The Cancer Genome Atlas (TCGA) to evaluate PTPN22 expression in NK cells and its association with clinical outcomes. We established a CRISPR-mediated PTPN22 knockout platform for NK cell gene editing and evaluated PTPN22 function using both genetic deletion and pharmacological inhibition across multiple NK cell platforms. Cytotoxicity and cytokine production were assessed against hematologic and solid tumor targets, including CD19⁺ and mesothelin-positive (MSLN⁺) cancer cells. PTPN22 knockout (PTPN22^KO) anti-CD19/CAR-NK92 cells were tested in Nalm6 xenograft models.

Published scRNA-seq datasets showed that PTPN22 was highly expressed in tumor-infiltrating NK cells. PTPN22^high NK cells exhibited stress and dysfunction signatures within inflammatory and immunosuppressive tumor microenvironments (TME), with elevated PTPN22 expression in TCGA associated with poorer patient survival. Genetic deletion of PTPN22 or pharmacological inhibition enhanced NK-cell cytotoxicity and pro-inflammatory cytokine release and improved the antitumor activity of chimeric antigen receptor (CAR)-NK cells against CD19⁺ and MSLN⁺ targets. PTPN22^KO preserved CAR-NK cell function under cytokine-based TME-like conditions and improved the functional persistence of primary anti-CD19 CAR-NK cells during prolonged tumor exposure. PTPN22^KO NK and CAR-NK cells showed increased or preserved signal transducer and activator of transcription 3 (STAT3) phosphorylation and reduced FAS expression under inflammatory conditions. Notably, PTPN22^KO anti-CD19/CAR-NK92 cells demonstrated superior anti-leukemic activity and significantly prolonged survival compared with non-knockout controls in vivo.

These findings identify PTPN22 as a novel intracellular checkpoint that limits NK and CAR-NK cell function. Targeted deletion of PTPN22 represents a promising strategy to enhance the therapeutic efficacy and persistence of both unmodified and CAR-engineered NK cells for cancer immunotherapy.

Treatment for advanced bladder cancer is rapidly evolving after decades of limited progress. Antibody-drug conjugates, targeted therapies, novel immunotherapy strategies, and innovative delivery platforms are reshaping management of both metastatic and muscle-invasive disease. This article focuses on promising new and novel agents, many of which are not yet standard of care, emphasizing their biological rationale and key clinical trial data to provide a forward-looking perspective on the future of bladder cancer management.

The role of surgery in the multimodal management of locally advanced and oligometastatic bladder cancer remains critical but incompletely defined. While current evidence is predominantly derived from retrospective series and institutional experiences, both metastasectomy and consolidative lymphadenectomy have demonstrated potential survival benefits in carefully selected patients following systemic therapy. However, interpretation of these data is hampered by the absence of standardized definitions, small and heterogeneous patient cohorts, and a lack of prospective, randomized trials. Ongoing clinical trials aim to refine patient selection criteria and clarify the role of surgery within modern therapeutic algorithms.

Bladder preservation utilizing maximal transurethral resection of the bladder tumor, radio sensitizing chemotherapy, and targeted pelvic radiation (known as Trimodal Therapy (TMT) is a validated treatment alternative for muscle invasive bladder cancer (MIBC) for appropriately selected and counseled patients. Long term results of the original studies that described TMT and continuing advancements in radiation techniques and chemo/immunotherapy regimens support its place in international treatment guidelines as more than a second line therapy for cystectomy ineligible patients. This review will provide an up-to-date discussion on the evidence supporting TMT for managing MIBC.