Open Access

REVIEW

Targeting the Tumor Microenvironment in Hodgkin Lymphoma: Challenges and Therapeutic Strategies

Filomena Emanuela Laddaga¹, Pamela Pinto², Bruna Daraia², Antonio D’amato^3,4, Stella D’oronzo^3,5, Stefano Martinotti^3,6,*, Francesco Gaudio^2,3,*

1 Hematology and Cell Therapy Unit, IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, 70124, Italy
2 Unit of Hematology, “F. Miulli” University Hospital, Bari, 70021, Italy
3 Department of Medicine and Surgery, LUM University “Giuseppe Degennaro”, Casamassima-Bari, 70010, Italy
4 Unit of Pathology, “F. Miulli” University Hospital, Bari, 70021, Italy
5 Unit of Oncology, “F. Miulli” University Hospital, Bari, 70021, Italy
6 Unit of Clinical Pathology, “F. Miulli” University Hospital, Bari, 70021, Italy

* Corresponding Authors: Stefano Martinotti. Email: ; Francesco Gaudio. Email:

(This article belongs to the Special Issue: Tumor Microenvironment in Molecular and Cellular Contexts)

BIOCELL 2025, 49(7), 1185-1206. https://doi.org/10.32604/biocell.2025.063572

Received 18 January 2025; Accepted 29 April 2025; Issue published 25 July 2025

Abstract

Checkpoint inhibitors, particularly programmed cell death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors, have significantly advanced the treatment of Hodgkin lymphoma (HL), especially in relapsed or refractory cases. However, challenges such as resistance, immune-related adverse events (irAEs), and the need for effective patient selection remain. This review aims to explore the mechanisms of resistance to checkpoint inhibitors, including alterations in the tumor microenvironment, loss of antigen presentation, and T-cell exhaustion. Overcoming resistance may involve combination therapies, such as pairing PD-1 inhibitors with other immune checkpoint inhibitors or targeted therapies like Brentuximab vedotin. Additionally, next-generation inhibitors targeting molecules like lymphocyte-activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) show promise in addressing resistance mechanisms not overcome by PD-1 inhibitors. Identifying reliable biomarkers to predict response to checkpoint inhibitors is critical for optimizing treatment, with ongoing research focusing on tumor mutational burden (TMB), inflammatory markers, and genetic profiling. Future clinical trials will aim to refine treatment regimens, optimize therapeutic combinations, and minimize adverse effects to maximize patient benefit.

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Keywords

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