Question explored with the scientific record
Conversation so far
- 1 can immunotherapy cause cancer to develop faster?
- 2 Are there any cases where immunotherapy clearly worsened tumor growth?
Answered on this page ↓
Are there any cases where immunotherapy clearly worsened tumor growth?
Yes. Immunotherapy can clearly worsen tumor growth in a subset of patients, and the phenomenon has a name: hyperprogressive disease (HPD).
The strongest evidence comes from a 2020 systematic review and meta-analysis of 1,389 non-small cell lung cancer patients treated with immune checkpoint inhibitors [2]. Across six retrospective studies, HPD incidence ranged from 8% to 30% of treated patients. Those who experienced HPD had significantly worse overall survival than patients who did not. The review identified five pre-treatment predictors: poor performance status (ECOG >1), high Royal Marsden Hospital score, elevated LDH, more than two metastatic sites, and liver metastasis [2]. This is not a rare fluke. In some subgroups, nearly one in three patients saw their tumors accelerate.
A 2025 study in ovarian cancer mouse models and human samples confirmed the mechanism [1]. When mice received anti-PD-1 alone, TIM-3 was upregulated on CD8+ T cells and tumor-infiltrating dendritic cells, and hyperprogression followed. Dual blockade of TIM-3 and PD-1 prevented HPD, delayed tumor growth, and improved survival [1]. This tells you HPD is a real, reproducible biological response to checkpoint blockade, not a measurement artifact.
The evidence also shows that immunotherapy can be actively harmful in specific subgroups. The mantle cell lymphoma study found PD-1 and PD-L1 expression too low to be relevant targets [3], meaning checkpoint inhibitors in that cancer are unlikely to help and carry the known toxicity risk without any offsetting benefit. The esophageal cancer study reported an objective response rate of only 23.8% [4], meaning three-quarters of patients got no tumor shrinkage while still being exposed to the drug's risks.
| Population | HPD incidence | Key predictor |
|---|---|---|
| NSCLC on ICIs [2] | 8–30% | Liver metastasis (OR 3.17) |
| HGSOC mouse model [1] | Prevented by dual blockade | TIM-3 upregulation |
| Mantle cell lymphoma [3] | PD-1/PD-L1 not relevant | Low target expression |
My call: hyperprogressive disease is a documented, clinically significant harm of checkpoint inhibitor immunotherapy, occurring in up to 30% of NSCLC patients and confirmed by mechanistic studies. Confidence: high for the existence of HPD; moderate for its incidence range, which varies by definition and tumor type.
Sources used 9
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Dual blockades of TIM-3 and PD-1 effectively prevent hyper-progression and enhance the efficacy of anti-PD-1 therapy in high-grade serous ovarian cancer
Dual blockade of TIM-3 and PD-1 prevents hyperprogression and enhances anti-PD-1 therapy in high-grade serous ovarian cancer by boosting CD8+ T cell and dendritic cell anti-tumor immunity in ID8-VEGF mouse models and ex vivo human samples.
DOI: 10.1038/s41419-025-08231-6 -
Clinical characteristics of hyperprogressive disease in NSCLC after treatment with immune checkpoint inhibitor: a systematic review and meta-analysis
This systematic review and meta-analysis quantifies the incidence, survival impact, and pre-treatment clinical predictors of hyperprogressive disease (HPD) in non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors (ICIs), highlighting five features…
DOI: 10.1186/s12885-020-07206-4 -
Expression of PD1 and PDL1 as immune-checkpoint inhibitors in mantle cell lymphoma
This study investigates the expression of PD-1 and PD-L1 as immune checkpoint inhibitors in mantle cell lymphoma (MCL) and concludes that they do not represent relevant targets for treatment, with age potentially impacting the effectiveness of immune checkpoint inhibitors.
DOI: 10.1186/s12885-022-09803-x -
Predicting the Efficacy of Immune Checkpoint Inhibitors in Esophageal Cancer: Changes in Peripheral Blood Lymphocyte Subsets Before and After Immunotherapy
This study investigates the predictive value of changes in peripheral blood lymphocyte subsets, particularly CD8+ T lymphocytes and NK cells, as biomarkers for the efficacy of immune checkpoint inhibitors in patients with esophageal cancer.
DOI: 10.2147/CMAR.S503171 -
Computational analysis of 4-1BB-induced NFκB signaling suggests improvements to CAR cell design
An ordinary differential equation–based model of canonical NF-κB signaling triggered by CD19scFv-4-1BB in CAR cells reveals a transient NF-κB activation with robust timing across antigen levels, identifies parameters that shape the response, and proposes engineering strategies (…
DOI: 10.1186/s12964-022-00937-w -
Expression Profiles of Five Common Cancer Membrane Protein Antigens Collected for the Development of Cocktail CAR-T Cell Therapies Applicable to Most Solid Cancer Patients
This study investigates the expression profiles of five common cancer membrane protein antigens (GPC3, ROBO1, EphB4, CLDN1, and LAT1) to develop cocktail CAR-T cell therapies that can effectively target a wide range of solid tumors.
DOI: 10.3390/ijms26052145 -
Potential strategies against resistance to CAR T-cell therapy in haematological malignancies
A comprehensive narrative review of resistance mechanisms to CAR T-cell therapy in hematologic malignancies and the evolving strategies to overcome it, including multi-target and armoured CAR designs, universal CARs, fully human CARs, microenvironment modulation, and combination…
DOI: 10.1177/1758835920962963 -
Precision sniper for solid tumors: CAR-NK cell therapy
A comprehensive review of CAR-NK cell therapy for solid tumors, detailing NK sources, CAR design generations, production/delivery methods, preclinical and clinical progress, and strategies to overcome tumor microenvironment barriers and safety concerns.
DOI: 10.1007/s00262-025-04106-z -
The Complexity of Targeting Chemokines to Promote a Tumor Immune Response
A comprehensive review detailing how chemokines and their receptors regulate immune cell infiltration into tumors, the implications for enhancing adoptive cell therapy and checkpoint inhibitors, and the preclinical and clinical evidence supporting chemokine-targeted cancer immun…
DOI: 10.1007/s10753-020-01235-8