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Cancer Immunotherapy: Focus on Immune Checkpoint Inhibitors and Immune Modulators

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (30 March 2026) | Viewed by 17702

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Special Issue Editor

Dr. Katsuaki Ieguchi

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Guest Editor

Department of Clinical Diagnostic Oncology, Clinical Research Institute for Clinical Pharmacology and Therapeutics, Showa University, Tokyo, Japan
Interests: PD-1; PD-L1; CTLA-4; immune checkpoint molecule; immune checkpoint inhibitor; tumor microenvironment; biomarker; bispecific T-cell engager; bispecific DC-T cell engager

Special Issue Information

Dear Colleagues,

Immune checkpoint inhibitors (ICIs), such as anti-PD-1 antibodies, disrupt interactions between immune checkpoint molecules and their ligands, thereby restoring T-cell-mediated cytotoxicity against tumor cells. ICIs are extensively employed in the treatment of various cancers, offering significant therapeutic benefits to patients. However, their efficacy is often limited, with some patients exhibiting resistance due to alternative immune evasion mechanisms. Additionally, current biomarkers for ICI-mediated therapy, including microsatellite instability and PD-L1 expression levels in tumors and lymphocytes, are insufficient for accurately predicting therapeutic outcomes. Therefore, addressing these limitations is crucial for enhancing the efficacy of ICIs in cancer treatment.

Emerging approaches, such as bispecific T-cell engagers (BiTEs) and combination therapies involving cytotoxic agents and ICIs, such as antibody–drug conjugates (ADCs), have led to remarkable improvements in efficacy. In current clinical settings, these combination therapies have shown promising outcomes and may represent the most effective strategy for improving ICI efficacy.

This Special Issue focuses on the molecular mechanisms underlying ICI treatment resistance, the identification and validation of biomarkers for predicting ICI efficacy, and strategies for improving ICI efficacy by modulating the tumor microenvironment. Additionally, discussions on preclinical tests involving small-molecule compounds, antibodies, and similar agents are welcome.

Dr. Katsuaki Ieguchi
Guest Editor

Manuscript Submission Information

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Keywords

PD-1
PD-L1
CTLA-4
immune checkpoint molecule
immune checkpoint inhibitor
tumor microenvironment
drug resistance
biomarker
BiTE
BiCE

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Published Papers (6 papers)

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Research

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9 pages, 427 KB

Open AccessArticle

Clinical Impact of Nivolumab in Sinonasal Mucosal Melanoma: A 14-Year Single-Center Retrospective Study and Comprehensive Literature Review

by Kosuke Terazawa, Ryo Utakata, Ryota Iinuma, Masashi Kuroki, Tatsuhiko Yamada, Hiromasa Ishihara, Ryo Kawaura, Hiroshi Okuda, Kenichi Mori, Hirofumi Shibata, Natsuko Obara, Miki Umeda, Ryoukichi Ikeda, Ken Saijo and Takenori Ogawa

Cancers 2026, 18(7), 1174; https://doi.org/10.3390/cancers18071174 - 6 Apr 2026

Viewed by 520

Abstract

Background: Sinonasal mucosal melanoma (SNMM) is a rare aggressive malignancy often resected with postoperative irradiation, with some evidence supporting the use of immune checkpoint inhibitors (ICIs). This study explores the potential efficacy and safety of nivolumab in 16 patients with SNMM, and reviews the literature of ICI use in it. Methods: We retrospectively analyzed 16 patients who had pathologically confirmed SNMM treated at Gifu University Hospital over a 14-year period between 2010 and 2024, of whom 11 received nivolumab. Clinical characteristics, treatment modalities, immune-related adverse events (irAEs), progression-free survival (PFS), and overall survival (OS) were examined. Kaplan–Meier and log-rank tests were used for survival analysis. A comprehensive literature review was done regarding ICI in SNMM. Results: Among the 16 patients, 11 received nivolumab and five did not. The nivolumab group showed longer median survival (median OS 26 mo vs. 8 mo; p = 0.00056) and a median PFS of 13 mo vs. 3 mo, p = 0.00175. In recurrent cases, nivolumab was associated with longer median OS (23 mo vs. 9 mo, p = 0.015) and PFS (11 mo vs. 3 mo, p = 0.019). irAEs occurred in four out of eleven of these cases, leading to nivolumab discontinuation; however, three of these four patients maintained durable disease control. A literature review identified generally favorable outcomes for ICIs in SNMM, although results were varied due to small sample sizes and heterogeneous treatment settings. Conclusions: Nivolumab was associated with longer survival in this small cohort in patients with SNMM, including those who discontinued therapy due to irAEs. Our data supports recent meta-analyses demonstrating a benefit of ICIs in SNMM. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Focus on Immune Checkpoint Inhibitors and Immune Modulators)

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21 pages, 552 KB

Open AccessArticle

Durvalumab-Based First-Line Chemoimmunotherapy in Advanced Biliary Tract Cancer: Real-World Outcomes and Prognostic Factors—A Turkish Oncology Group Study

by Safa Can Efil, Fatih Kus, Bahadir Koylu, Bekir Mert Durukan, Selami Bayram, Halil Goksel Guzel, Banu Ozturk, Harun Muglu, Ahmet Bilici, Fatih Kose, Ozkan Alan, Eda Karapelit Agitoglu, Gurkan Guner, Ali Ayberk Besen, Kaan Helvaci, Murat Araz, Turgut Kacan, Cagatay Arslan, Ahmet Unal, Emine Bihter Eniseler, Sedat Biter, Ferhat Ekinci, Ferit Aslan, Ilkay Tugba Unek, Semra Tas, Omer Acar, Ozturk Ates, Teoman Sakalar, Sinem Akbas, Hilal Karakas, Muhammed Bulent Akinci, Bulent Yalcin, Suayip Yalcin and Mehmet Ali Nahit Sendur Show full author list Hide full author list

Cancers 2026, 18(1), 101; https://doi.org/10.3390/cancers18010101 - 29 Dec 2025

Viewed by 942

Abstract

Background: Durvalumab combined with gemcitabine–cisplatin (GC) has become the standard first-line treatment for advanced biliary tract cancer (BTC) following the TOPAZ-1 trial. However, real-world effectiveness, safety, and prognostic determinants, particularly in underrepresented populations, remain insufficiently defined. The aim of this study was to evaluate the real-world outcomes of first-line durvalumab plus chemotherapy and identify independent prognostic factors in patients with advanced BTC. Methods: This multicenter retrospective cohort study included patients with unresectable or metastatic BTC treated with first-line durvalumab plus chemotherapy across 21 tertiary oncology centers in Türkiye. Clinical characteristics, laboratory parameters, biomarker data, and treatment details were collected. The primary endpoint was overall survival (OS), while secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and safety. Survival outcomes were analyzed using the Kaplan–Meier method and Cox proportional hazards regression models. Results: A total of 78 patients were analyzed; 53.8% were male, and the median age was 62 years. Primary tumor sites were intrahepatic (55.1%), extrahepatic (30.8%), and gallbladder (14.1%). After a median follow-up of 12.58 months, median OS was 11.59 months and median PFS was 6.80 months. The ORR was 50.6%, including complete and partial responses in 2.7% and 47.9% of patients, respectively. Treatment-related adverse events occurred in 97.4% of patients, with grade 3–4 events in 37.2%. Immune-related adverse events were observed in 19.2%, including one case of grade 3 pneumonitis. No patient permanently discontinued durvalumab due to toxicity, and no durvalumab-related mortality occurred. In multivariable analysis, ECOG performance status 2 (HR 3.43; 95% CI 1.33–8.80) and ALBI grade 2–3 (HR 2.54; 95% CI 1.24–5.19) independently predicted worse OS, while ECOG performance status 2 also predicted shorter PFS (HR 5.91; 95% CI 2.30–15.17). Conclusions: In this multicenter real-world Turkish cohort, first-line durvalumab plus chemotherapy showed effectiveness and tolerability comparable to clinical trial data. Baseline ECOG performance status and ALBI grade were independent prognostic factors, supporting their use for risk stratification in advanced biliary tract cancer. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Focus on Immune Checkpoint Inhibitors and Immune Modulators)

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14 pages, 1865 KB

Open AccessArticle

Plasma WFDC2 (HE4) as a Predictive Biomarker for Clinical Outcomes in Cancer Patients Receiving Anti-PD-1 Therapy: A Pilot Study

by Makoto Watanabe, Katsuaki Ieguchi, Takashi Shimizu, Ryotaro Ohkuma, Risako Suzuki, Emiko Mura, Nana Iriguchi, Tomoyuki Ishiguro, Yuya Hirasawa, Go Ikeda, Masahiro Shimokawa, Hirotsugu Ariizumi, Kiyoshi Yoshimura, Atsushi Horiike, Takuya Tsunoda, Mayumi Tsuji, Shinichi Kobayashi, Tatsunori Oguchi, Yuji Kiuchi and Satoshi Wada

Cancers 2025, 17(14), 2384; https://doi.org/10.3390/cancers17142384 - 18 Jul 2025

Cited by 1 | Viewed by 1851

Abstract

Background/Objectives: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy; however, reliable biomarkers of therapeutic efficacy remain limited. We investigated the clinical utility of plasma WFDC2 levels in patients receiving anti-PD-1 antibody treatment. Methods: Twenty-one patients with non-small cell lung, gastric, or bladder cancer received nivolumab or pembrolizumab. Plasma WFDC2 concentrations were measured by ELISA before ICI treatment (pre-ICI) and after two and four treatment cycles. Associations between WFDC2 expression changes and overall survival (OS), progression-free survival (PFS), and tumor progression were assessed. ROC curve analyses compared the predictive performance of WFDC2, soluble PD-L1 (sPD-L1), soluble PD-1 (sPD-1), and their combinations, with the area under the curve (AUC) evaluating predictive accuracy. Results: Levels of WFDC2 pre-ICI and those after two cycles were significantly higher than levels in healthy donors. However, no significant differences in WFDC2 levels were found between the time points during treatment. Greater increases in WFDC2 levels were significantly correlated with shorter OS (p = 0.002), shorter PFS (p = 0.037), and tumor progression (p = 0.003). ROC analysis revealed that WFDC2 achieved a higher AUC (0.700) than sPD-L1 (0.538) or sPD-1 (0.650). Combining biomarkers improved the predictive accuracy, with sPD-L1 plus WFDC2 showing the highest AUC (0.825). Conclusions: Serial increases in plasma WFDC2 are associated with poor clinical outcomes, highlighting its potential as a biomarker. Baseline plasma WFDC2 outperformed sPD-L1 and sPD-1 diagnostically. These findings should be interpreted as exploratory and hypothesis-generating, requiring confirmation in larger, tumor-specific cohorts with multivariate adjustment. WFDC2 represents a promising minimally invasive biomarker for the early identification of patients unlikely to benefit from ICI therapy. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Focus on Immune Checkpoint Inhibitors and Immune Modulators)

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21 pages, 2769 KB

Open AccessArticle

IOS-1002, a Stabilized HLA-B57 Open Format, Exerts Potent Anti-Tumor Activity

by Anahita Rafiei, Marco Gualandi, Chia-Lung Yang, Richard Woods, Anil Kumar, Kathrin Brunner, John Sigrist, Hilmar Ebersbach, Steve Coats, Christoph Renner and Osiris Marroquin Belaunzaran

Cancers 2024, 16(16), 2902; https://doi.org/10.3390/cancers16162902 - 21 Aug 2024

Cited by 2 | Viewed by 3459

Abstract

HLA-B27 and HLA-B57 are associated with autoimmunity and long-term viral control and protection against HIV and HCV infection; however, their role in cancer immunity remains unknown. HLA class I molecules interact with innate checkpoint receptors of the LILRA, LILRB and KIR families present in diverse sets of immune cells. Here, we demonstrate that an open format (peptide free conformation) and expression- and stability-optimized HLA-B57-B2m-IgG4_Fc fusion protein (IOS-1002) binds to human leukocyte immunoglobulin-like receptor B1 and B2 (LILRB1 and LILRB2) and to killer immunoglobulin-like receptor 3DL1 (KIR3DL1). In addition, we show that the IgG4 Fc backbone is required for engagement to Fcγ receptors and potent activation of macrophage phagocytosis. IOS-1002 blocks the immunosuppressive ITIM and SHP1/2 phosphatase signaling cascade, reduces the expression of immunosuppressive M2-like polarization markers of macrophages and differentiation of monocytes to myeloid-derived suppressor cells, enhances tumor cell phagocytosis in vitro and potentiates activation of T and NK cells. Lastly, IOS-1002 demonstrates efficacy in an ex vivo patient-derived tumor sample tumoroid model. IOS-1002 is a first-in-class multi-target and multi-functional human-derived HLA molecule that activates anti-tumor immunity and is currently under clinical evaluation. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Focus on Immune Checkpoint Inhibitors and Immune Modulators)

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Review

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21 pages, 1952 KB

Open AccessReview

Programmed Death-1 Ligand 1 Domain Organization, Signaling Motifs, and Interactors in Cancer Immunotherapy

by David Escors, Luisa Chocarro, Miriam Echaide, Claudia Rodriguez-Neira, Borja Vilaplana and Grazyna Kochan

Cancers 2025, 17(10), 1635; https://doi.org/10.3390/cancers17101635 - 12 May 2025

Cited by 5 | Viewed by 3223

Abstract

Immunotherapies targeting the programmed cell death-1 ligand 1 (PD-L1) and programmed cell death 1 (PD-1) pathway sparked a revolution in cancer treatment. These breakthrough therapies work by disrupting the interaction between PD-1—expressed on T cells—and its ligand PD-L1, commonly found on the surface of cancer cells. By using monoclonal antibodies to block this binding, the immune system is unleashed to fight cancer more effectively. However, PD-L1’s role extends far beyond immune evasion. When situated on cancer cells, PD-L1 transmits inhibitory signals through PD-1, silencing the effector functions of T cells. However, PD-L1 also engages in reverse signaling, also called intrinsic signaling, delivering intracellular instructions that contribute to cancer cell survival, even in the absence of PD-1 binding. This signaling cascade shields cancer cells from apoptosis, drives proliferation, regulates DNA damage responses, and even functions as a co-transcriptional transactivator, amplifying cancer’s ability to thrive. The intricate mechanisms behind PD-L1’s intrinsic signaling are under intense investigation. In this review, we provide a historical perspective on the discoveries leading to PD-L1’s structure, signaling motifs, and interacting partners, shedding light on its multifaceted roles and the promising therapeutic possibilities ahead. Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Focus on Immune Checkpoint Inhibitors and Immune Modulators)

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63 pages, 5843 KB

Open AccessReview

Revolutionary Cancer Therapy for Personalization and Improved Efficacy: Strategies to Overcome Resistance to Immune Checkpoint Inhibitor Therapy

by Saud Almawash

Cancers 2025, 17(5), 880; https://doi.org/10.3390/cancers17050880 - 4 Mar 2025

Cited by 32 | Viewed by 6616

Abstract

Cancer remains a significant public health issue worldwide, standing as a primary contributor to global mortality, accounting for approximately 10 million fatalities in 2020 [...] Full article

(This article belongs to the Special Issue Cancer Immunotherapy: Focus on Immune Checkpoint Inhibitors and Immune Modulators)

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