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Pharmaceuticals
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Comprehensive Strategies in Cancer Immunotherapy
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Comprehensive Strategies in Cancer Immunotherapy

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 31 May 2026 | Viewed by 5191

Special Issue Editor

Dr. Yee Peng Phoon

E-Mail Website
Guest Editor
Cleveland Clinic Foundation, Cleveland, OH, USA
Interests: immunotherapy; biomarkers; immuno-oncology

Special Issue Information

Dear Colleagues,

Cancer immunotherapy has evolved significantly over the past century, beginning with early theories and experimental treatments, and progressing to the modern era, which is marked by groundbreaking innovations like immune checkpoint inhibitors, CAR-T therapies, TIL therapy, and cancer vaccines. These advancements have fundamentally shifted the paradigm of cancer patient management. Today, immunotherapy stands at the forefront of cancer treatment, ushering in a new era that offers renewed hope to patients.

Despite these recent breakthroughs, cancer continues to pose a major global challenge. It is projected that by 2025, there will be approximately 26 million new cancer cases worldwide, along with 17 million cancer-related deaths. This stark reality underscores the need for more comprehensive treatment strategies that can bridge current gaps—specifically, the discovery and development of new modalities aimed at improving clinical outcomes and providing sustainable benefits for patients.

As research delves deeper into the mechanisms governing immune cell function and their interactions with the tumor microenvironment, even more promising therapeutic options are on the horizon. The field of neoadjuvant therapy has gained significant attention, with ongoing clinical trials and innovative approaches focused on improving clinical outcomes across a range of cancer types. Additionally, there has been a renewed interest in cytokine therapy and bispecific antibodies, which show great promise when used in combination therapies to enhance anti-tumor efficacy.

Another key area of focus is the development of predictive biomarkers to forecast treatment responses. Integrating these biomarkers into clinical practice has the potential to be one of the most transformative advancements in cancer care, reshaping diagnosis, treatment selection, and the timing of interventions.

In conclusion, the future of cancer treatment and management lies in the integration of combination therapies and predictive biomarkers to enable more personalized, targeted, and effective treatments, ultimately leading to better outcomes and advancing the overall quality of healthcare.

Dr. Yee Peng Phoon
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • immunotherapy
  • CAR-T
  • TIL therapy
  • predictive biomarker
  • neoadjuvant
  • cytokine therapy
  • bispecific antibodies
  • personalized treatment
  • combination therapies
  • tumor microenvironment
  • immune modulation, interaction and mechanism

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Published Papers (5 papers)

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Review

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21 pages, 1868 KB  
Review
Broad-Spectrum RAS Inhibition in Pancreatic Ductal Adenocarcinoma: Mechanistic Advances and Therapeutic Promise
by Fawaz E. Alanazi, Yasser Alatawi, Abdullah Alattar, Reem Alshaman, Ahmed A. Kotb and Helal F. Hetta
Pharmaceuticals 2025, 18(12), 1788; https://doi.org/10.3390/ph18121788 - 24 Nov 2025
Viewed by 998
Abstract
The RAS family of oncoproteins (KRAS, HRAS, and NRAS) drive aggressive cancers like pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC), yet targeting mutant RAS has historically been challenging due to its “undruggable” structure. Recent advances in mutation-specific inhibitors (e.g., sotorasib [...] Read more.
The RAS family of oncoproteins (KRAS, HRAS, and NRAS) drive aggressive cancers like pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer (NSCLC), yet targeting mutant RAS has historically been challenging due to its “undruggable” structure. Recent advances in mutation-specific inhibitors (e.g., sotorasib for KRASG12C) have demonstrated clinical efficacy but face limitations in tumor types like PDAC, where KRASG12C mutations are rare. Broad-spectrum pan-RAS inhibitors (e.g., RMC-7977, RMC-6236, ADT-007/ADT-1004) now offer promise by targeting active GTP-bound or nucleotide-free RAS across isoforms and mutations. Preclinical studies show these agents induce deep tumor regressions, overcome resistance to allele-specific inhibitors, and remodel the tumor microenvironment (TME) by enhancing T-cell infiltration and reducing immunosuppressive myeloid cells. Early clinical data for RMC-6236 report disease control rates of 85–87% in NSCLC and PDAC, with manageable toxicity. This review shows that pan-RAS inhibitors represent a promising new class of therapeutics capable of overcoming many historical challenges associated with the “undruggable” nature of RAS proteins and demonstrating encouraging preclinical and early clinical results, particularly in difficult-to-treat tumor types such as PDAC and NSCLC. Challenges remain in achieving a therapeutic index due to RAS’s role in normal tissue homeostasis, but tumor-specific drug accumulation and rapid normal tissue recovery may mitigate risks. Ongoing trials are evaluating combination strategies with immunotherapy and chemotherapy, positioning pan-RAS inhibitors as transformative agents for RAS-driven cancers. Full article
(This article belongs to the Special Issue Comprehensive Strategies in Cancer Immunotherapy)
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26 pages, 3289 KB  
Review
BTLA: An Emerging Immune Checkpoint Target in Cancer Immunotherapy
by Ming-Cheng Chang, Wan-Chi Lee, Yi-Jou Tai and Ying-Cheng Chiang
Pharmaceuticals 2025, 18(12), 1784; https://doi.org/10.3390/ph18121784 - 24 Nov 2025
Viewed by 826
Abstract
B and T lymphocyte attenuator (BTLA) is a unique co-inhibitory receptor of the CD28 immunoglobulin superfamily that exhibits dual regulatory functions in immune activation and tolerance. Unlike PD-1 or CTLA-4, BTLA interacts bidirectionally with its ligand HVEM, forming a complex signaling network that [...] Read more.
B and T lymphocyte attenuator (BTLA) is a unique co-inhibitory receptor of the CD28 immunoglobulin superfamily that exhibits dual regulatory functions in immune activation and tolerance. Unlike PD-1 or CTLA-4, BTLA interacts bidirectionally with its ligand HVEM, forming a complex signaling network that shapes immune homeostasis within the tumor microenvironment. Dysregulated BTLA expression has been associated with tumor immune evasion and poor prognosis in several cancers. Owing to its distinctive molecular features and multifaceted immunoregulatory roles, BTLA represents an emerging therapeutic target, particularly in tumors unresponsive to conventional immune checkpoint inhibitors. This review provides a comprehensive overview of BTLA’s structure, signaling mechanisms, and functional implications in tumor immunity and discusses current advances and challenges in BTLA-targeted therapy. Finally, we outline future perspectives on leveraging BTLA modulation to enhance cancer immunotherapy outcomes. Full article
(This article belongs to the Special Issue Comprehensive Strategies in Cancer Immunotherapy)
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27 pages, 2047 KB  
Review
Harnessing Single-Cell RNA-Seq for Computational Drug Repurposing in Cancer Immunotherapy
by Olivia J. Cheng, T.T.T. Tran, Y. Ann Chen and Aik Choon Tan
Pharmaceuticals 2025, 18(11), 1769; https://doi.org/10.3390/ph18111769 - 20 Nov 2025
Viewed by 977
Abstract
Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment and show notable success in some cancer types such as non-small cell lung cancer, melanoma and colorectal cancers, while they demonstrate relatively low response rate in others, such as esophageal cancers. Due to the heterogeneous [...] Read more.
Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment and show notable success in some cancer types such as non-small cell lung cancer, melanoma and colorectal cancers, while they demonstrate relatively low response rate in others, such as esophageal cancers. Due to the heterogeneous nature of the tumor microenvironment and patient-to-patient variability, there remains a need to improve ICI response rates. Combining ICIs with therapies that can overcome resistance is a promising strategy. Compared to de novo drug development, drug repurposing offers a faster and more cost-effective approach to identifying such combination candidates. A variety of computational drug repurposing tools leverage genomics and/or transcriptomic data. As single-cell RNA sequencing (scRNA-seq) technology becomes available, it enables precise targeting of cancer-driving cellular components. In this review, we highlight current computational drug repurposing tools utilizing scRNA-seq data and demonstrate the application of two such tools, scDrug and scDrugPrio, on an esophageal squamous cell carcinoma dataset to identify potential drug candidates for combination with ICI therapy to enhance treatment response. scDrug focuses on predicting tumor cell-specific cytotoxicity, while scDrugPrio prioritizes drugs by reversing gene signatures associated with ICI non-responsiveness across diverse tumor microenvironment cell types. Together, this review underscores the importance of a multi-faceted approach in computational drug repurposing and highlights its potential for identifying drugs that enhance ICI treatment. Future work can expand the application of these strategies to multi-omics and spatial transcriptomics datasets, as well as personalized patient samples, to further refine drug repurposing involving ICI therapy. Full article
(This article belongs to the Special Issue Comprehensive Strategies in Cancer Immunotherapy)
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21 pages, 3209 KB  
Systematic Review
Therapeutic Impact of Zanubrutinib in Chronic Lymphocytic Leukemia: Evidence from a Systematic Review and Single-Arm Meta-Analysis
by Yasser Alatawi, Fawaz E. Alanazi, Abdullah Alattar, Reem Alshaman, Yasmin N. Ramadan, Reem Sayad and Helal F. Hetta
Pharmaceuticals 2025, 18(11), 1674; https://doi.org/10.3390/ph18111674 - 5 Nov 2025
Viewed by 827
Abstract
Background and Objective: Zanubrutinib, a next-generation Bruton’s tyrosine kinase inhibitor (BTKi), has demonstrated promising efficacy in chronic lymphocytic leukemia (CLL), including treatment-naïve (TN) and relapsed/refractory (R/R) patients. However, evidence synthesis across clinical trials remains limited. We conducted a systematic review and single-arm meta-analysis [...] Read more.
Background and Objective: Zanubrutinib, a next-generation Bruton’s tyrosine kinase inhibitor (BTKi), has demonstrated promising efficacy in chronic lymphocytic leukemia (CLL), including treatment-naïve (TN) and relapsed/refractory (R/R) patients. However, evidence synthesis across clinical trials remains limited. We conducted a systematic review and single-arm meta-analysis to evaluate the efficacy of zanubrutinib in CLL. Methods: This study was performed in accordance with PRISMA guidelines and Cochrane recommendations. PubMed, Medline, Scopus, and Web of Science were searched up to August 2025 using terms related to zanubrutinib and CLL/SLL. Eligible studies included clinical trials of zanubrutinib in TN or R/R CLL/SLL patients. Risk of bias was assessed using the JBI tool for non-randomized studies and for RCTs. Pooled estimates of efficacy outcomes were calculated using a random-effects model. Pooled estimates were calculated using the DerSimonian–Laird random-effects model, which accounts for both within- and between-study variability. Results: Seven studies (n > 1000) were included, enrolling both TN and R/R patients across diverse global populations. The pooled overall response rate (ORR) was 93.3% (95% CI, 86.7–99.8%) in mixed TN and R/R populations, 94.4% (95% CI, 91.6–97.3%) in TN patients, and 83.9% (95% CI, 75.0–92.8%) in R/R patients. Complete response (CR) rates were 12.2% (95% CI, 0.3–24.2%) overall, 13.8% (95% CI, 1.5–26.2%) in TN patients, and 5.0% (95% CI, 0.3–9.8%) in R/R patients. Partial response (PR) rates reached 86.0% (95% CI, 82.6–89.5%) in TN and 63.2% (95% CI, 53.5–73.0%) in R/R patients. Progressive disease was rare (≤1% in R/R cohorts). Heterogeneity was moderate to high across several outcomes. Conclusions: Zanubrutinib demonstrates favorable efficacy in CLL, achieving high ORR in both TN and R/R patients, with particularly durable responses in TN populations. Although complete response rates remain modest, especially among R/R patients, overall disease control appears consistent. These findings support zanubrutinib as an effective treatment option across CLL settings; however, variability among studies and the modest CR rates highlight the need for longer follow-up and direct comparative trials to further define its clinical role. Full article
(This article belongs to the Special Issue Comprehensive Strategies in Cancer Immunotherapy)
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17 pages, 758 KB  
Systematic Review
Evaluating the Safety and Efficacy of PD-1 Inhibitors in HIV Patients Diagnosed with Lung Cancer: A Systematic Review
by Helal F. Hetta, Yasser Alatawi, Fawaz E. Alanazi, Abdullah Alattar, Reem Alshaman, Hanan Alshareef, Zinab Alatawi, Majd S. Alatawi, Jumana H. Albalawi, Ghadeer A. Alosaimi, Reem Sayad and Wedad M. Nageeb
Pharmaceuticals 2025, 18(11), 1654; https://doi.org/10.3390/ph18111654 - 1 Nov 2025
Viewed by 827
Abstract
Background and Aim: People with HIV (PWH) have historically been excluded from cancer immunotherapy trials due to concerns over immune dysregulation and safety. This systematic review evaluates the safety, efficacy, and immunologic outcomes of Programmed death-1 (PD-1) inhibitors in PWH diagnosed with [...] Read more.
Background and Aim: People with HIV (PWH) have historically been excluded from cancer immunotherapy trials due to concerns over immune dysregulation and safety. This systematic review evaluates the safety, efficacy, and immunologic outcomes of Programmed death-1 (PD-1) inhibitors in PWH diagnosed with non-small-cell lung cancer (NSCLC). Methods: Following PRISMA guidelines, a systematic search was conducted across PubMed, Scopus, Web of Science, and Medline through January 2025. Studies were included if they reported outcomes of ICIs in PWH with NSCLC. Data extraction included progression-free survival (PFS), overall survival (OS), immune-related adverse events (irAEs), antitumor response, HIV viral control, and immunologic parameters. Study quality was assessed using the Joanna Briggs Institute (JBI) checklist. Results: Six cohort studies (n = 762 patients) met inclusion criteria. ICIs used included nivolumab, pembrolizumab, atezolizumab, and durvalumab, with treatment durations ranging from 3.1 to 5.4 months. Median PFS ranged from 3.0 to 6.3 months, and OS ranged from 10.0 to 66.0 months. Overall response rates (ORRs) varied from 13% to 75%, and disease control rates (DCRs) ranged from 47% to 62.5%. irAEs occurred in 25% to 75% of patients, with 6–20% experiencing grade 3–4 events. Corticosteroids were required in 13–29% of patients, and treatment discontinuation due to toxicity occurred in up to 30%. Most patients had controlled HIV, with CD4 counts typically above 300 cells/μL and undetectable viral loads. Conclusions: ICIs appear safe and effective in PWH with NSCLC, with toxicity and efficacy outcomes comparable to the general population. While immunotherapy should not be withheld based solely on HIV status, better standardization in reporting HIV-related variables is needed to optimize patient selection and management. Full article
(This article belongs to the Special Issue Comprehensive Strategies in Cancer Immunotherapy)
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