# Beyond PD‐1: Mechanisms of Resistance to Checkpoint Blockade in Classical Hodgkin Lymphoma and Next‐Generation Immune Strategies

## TL;DR

This paper reviews why some classical Hodgkin lymphoma patients resist PD-1 inhibitors and explores new strategies to overcome this resistance.

## Contribution

The paper introduces emerging biomarkers and novel therapeutic strategies to address PD-1 resistance in classical Hodgkin lymphoma.

## Key findings

- Tumor-intrinsic and microenvironmental factors contribute to PD-1 resistance in classical Hodgkin lymphoma.
- Biomarkers like PET response and ctDNA can help identify nonresponders early.
- Combination therapies targeting macrophages and immune checkpoints show promise in resistant cases.

## Abstract

PD‐1 inhibitors have reshaped the treatment landscape of classical Hodgkin lymphoma, yet a substantial proportion of patients exhibit primary or acquired resistance driven by tumor‐intrinsic alterations, immunosuppressive microenvironmental signals, metabolic constraints, and EBV‐mediated modulation. This review summarizes key mechanisms underlying PD‐1 resistance and highlights emerging biomarkers—including early 18F‐FDG PET response, circulating tumor DNA kinetics, molecular subtyping, and spatial immune profiling—that enable early identification of nonresponders and support precision immunotherapy. Novel therapeutic strategies such as macrophage‐targeted agents, metabolic modulators, bispecific antibodies, low‐dose PD‐1 regimens, and CD30‐directed CAR‐T cells show promise in overcoming resistance, particularly when integrated into adaptive, biomarker‐guided treatment algorithms. Early incorporation of PET and ctDNA monitoring may inform timely treatment adaptation, while combination approaches addressing macrophage‐driven suppression or redundant immune checkpoints should be considered in biologically high‐risk patients. Overall, a deeper mechanistic understanding coupled with biomarker‐driven stratification is essential to optimize PD‐1‐based therapy and improve long‐term outcomes in cHL.