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Emerging Therapeutic Strategies and Immunometabolic Pathways in Cancer

A Special Issue of International Journal of Molecular Sciences (ISSN 1422-0067) belonging to the section "Molecular Immunology".

Deadline for manuscript submissions: 30 April 2027 | Viewed by 2221

Editor


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Guest Editor
1. Department of Veterans Affairs, Miami VA Healthcare System, Miami, FL 33125, USA
2. Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL 33136, USA
3. South Florida VA Foundation for Research and Education, Miami, FL 33125, USA
4. Department of Surgery, Division of Thoracic Surgery, University of Miami, Miami, FL 33136, USA
Interests: platinum-resistant lung cancer; cisplatin; carboplatin resistant

Special Issue Information

Dear Colleagues,

The intricate interplay between tumor metabolism and immune evasion has established a transformative frontier in cancer therapy. As traditional approaches are challenged by drug resistance and limited durability, emerging strategies integrating targeted therapies with immunomodulation offer new hope. This Special Issue highlights the converging evidence that metabolic reprogramming, characterized by altered metabolism, not only sustains malignant growth but also reshapes the tumor immune microenvironment. Recent studies demonstrate that therapies targeting oncogenic signaling pathways, such as MYC, KRAS, and PI3K, can enhance tumor antigenicity and T-cell infiltration when combined with immune checkpoint blockade. Moreover, efforts to convert “cold” tumors into “hot” ones through modulation of the tumor microenvironment or the activation of innate immune pathways have shown promise in augmenting immunotherapeutic efficacy. Cellular therapies, including CAR-T and engineered NK cells, are being redesigned to overcome metabolic suppression within solid tumors. Collectively, these advances underscore the necessity of integrative, metabolism-informed approaches to immunotherapy.

This Special Issue brings together novel mechanistic insights, preclinical models, and translational strategies that will inform the next generation of combination treatments aimed at overcoming resistance and improving patient outcomes across diverse malignancies.

Dr. Medhi Wangpaichitr
Guest Editor

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Keywords

  • immunotherapy
  • targeted therapy
  • tumor metabolism pathway
  • tumor microenvironment
  • immune checkpoint blockade
  • immune evasion
  • glucose/amino acids/lipid metabolism

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Published Papers (2 papers)

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Research

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19 pages, 7479 KB  
Article
Integrated Single-Cell Analysis Identifies IL1RAP as a Master Regulator of TAMs and a Prognostic Biomarker in Breast Cancer
by Wucheng Zhu, Gaoge Peng, Yi Wu, Lixing Zhang, Mingang He, Beibei Xin, Wei Jin and Hefen Sun
Int. J. Mol. Sci. 2026, 27(4), 1894; https://doi.org/10.3390/ijms27041894 - 16 Feb 2026
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Abstract
The recruitment and polarization of tumor-associated macrophages (TAMs) play a pivotal role in shaping the immunosuppressive tumor microenvironment in breast cancer. Interleukin-1 receptor accessory protein (IL1RAP), a critical co-receptor for IL-1 family cytokines, is emerging as a potential regulator of macrophage function, though [...] Read more.
The recruitment and polarization of tumor-associated macrophages (TAMs) play a pivotal role in shaping the immunosuppressive tumor microenvironment in breast cancer. Interleukin-1 receptor accessory protein (IL1RAP), a critical co-receptor for IL-1 family cytokines, is emerging as a potential regulator of macrophage function, though its specific role in TAM biology remains to be explained. In this study, we investigated the impact of IL1RAP on macrophage recruitment and M2-like polarization. Initial bioinformatics analysis of public databases revealed a significant correlation between elevated IL1RAP expression in macrophages and signatures of immune suppression and poor prognosis in breast cancer. To functionally validate these findings, we performed IL1RAP knockdown in a murine macrophage cell line. Our results demonstrated that IL1RAP deficiency markedly impaired the migratory capacity of macrophages towards classic chemotactic stimuli. Furthermore, under M2-polarizing conditions, IL1RAP-knockdown macrophages exhibited a significantly attenuated M2 phenotype, as evidenced by the decreased expression of canonical M2 markers (e.g., Arg1, Mrc1) and reduced functional outputs. Collectively, our integrated approach combining bioinformatics and in vitro experimentation identifies IL1RAP as a novel regulator that potentiates both the recruitment and the M2 polarization of macrophages. These findings suggest that targeting the IL1RAP pathway could represent a promising therapeutic strategy for reprogramming the tumor-immune microenvironment by limiting pro-tumoral macrophage infiltration and polarization. Full article
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Review

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14 pages, 4864 KB  
Review
The Tryptophan Paradox: From Microbiome-Mediated Homeostasis to Tumor-Driven Immune Escape
by Alexis Cho, Chunjing Wu, George Theodoropoulos, Manojavan Nagarajan, Adeline M. Murphy, Karli F. Heller, Niramol Savaraj, Theodore J. Lampidis and Medhi Wangpaichitr
Int. J. Mol. Sci. 2026, 27(10), 4296; https://doi.org/10.3390/ijms27104296 - 12 May 2026
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Abstract
Tryptophan (Trp) metabolism sits at the intersection of nutrition, the microbiome, mucosal immunity, and tumor adaptation. The broad observation that microbial indoles can support barrier function, whereas tumors exploit kynurenine-pathway metabolism to suppress immunity, is already established in publications. The specific contribution of [...] Read more.
Tryptophan (Trp) metabolism sits at the intersection of nutrition, the microbiome, mucosal immunity, and tumor adaptation. The broad observation that microbial indoles can support barrier function, whereas tumors exploit kynurenine-pathway metabolism to suppress immunity, is already established in publications. The specific contribution of this review is to organize that literature into a context- and network-based translational framework. Rather than treating indoleamine 2,3-dioxygenase 1 (IDO1) as a single bottleneck, we frame tumor Trp metabolism as a compensatory system linking IDO1, tryptophan 2,3-dioxygenase (TDO2), interleukin-4-induced gene 1 (IL4I1), amino-acid transport, amino-acid stress sensing, and downstream aryl hydrocarbon receptor (AHR) signaling. In healthy tissue, especially the gut, dietary Trp and microbiota-derived indoles can promote epithelial integrity, interleukin-22 (IL-22)-associated programs, and mucosal restraint. In tumors, the same substrate pool is redirected toward Kynurenine, kynurenic acid, indole-3-pyruvate, and related catabolites that impair cytotoxic lymphocytes, expand regulatory T-cell (Treg) and suppressive myeloid compartments, and reinforce invasion and treatment resistance. We also argue that the potential metabolite biomarker interpretation should be context-dependent. Finally, we propose a clinical-context–specific framework for intervention. Dietary and microbiome-based strategies may be most effective in prevention, premalignant states, or supportive care, whereas established cancers are more likely to require biomarker-guided targeting of tumor-associated catabolic pathways and convergent signaling mechanisms. The “paradox” is therefore not that Trp changes chemistry across settings, but that the same nutrient is routed through different cellular contexts, enzymes, ligands, and cell states. Full article
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