Whilst immunotherapy has transformed the management of several solid tumours, its impact in prostate cancer has remained very limited. Today, the benefit is confined to sipuleucel-T for selected patients with metastatic castration-resistant prostate cancer (mCRPC) and PD-1 blockade for those with mismatch repair deficient (dMMR)/microsatellite instability–high (MSI-H) tumours. Outside of these niches, clinical benefit remains elusive.
The biological landscape of prostate cancer helps explain its resistance to immunotherapy: tumours generally exhibit low mutational burden, limited neoantigen expression, and a profoundly immunosuppressive tumour immune microenvironment (TIME) enriched with regulatory T cells, myeloid-derived suppressor cells, and inhibitory cytokines. Collectively, these features underlie the poor efficacy of conventional checkpoint blockade.
Current Evidence:
We examined the available data and found that sipuleucel-T remains the only immunotherapy approved for prostate cancer specifically, offering a modest overall survival benefit (~4 months in a pivotal phase III trial) in men with asymptomatic or minimally symptomatic castration-resistant disease. Enthusiasm for broader adoption of immunotherapy has been dampened by repeated negative phase II and III studies of checkpoint inhibitors.
A small subset of prostate cancers (~3-4%) characterised by dMMR/MSI-H status can achieve dramatic and long-lasting benefit from PD-1 blockade. We recognised that these “exceptional responders” highlight the importance of biomarker-driven patient selection.
Emerging Strategies:
This paper highlights how the field is shifting to newer therapies that may expand clinical benefit beyond rare subgroups. Specifically, we focused on the development of T-cell engagers (TCEs) and chimeric antigen receptor (CAR)-T cell therapies. Among the most promising therapeutic targets are PSMA, STEAP1, PSCA, hK2, and TMEFF2.
TCEs can redirect cytotoxic T cells directly toward prostate cancer cells, circumventing established mechanisms of immune evasion. Early-phase trials have produced encouraging PSA and radiographic responses. Importantly, lessons from challenges such as cytokine-release syndrome and neutralising anti-drug antibodies have shaped ongoing development. A key milestone is the launch of a Phase III trial of the novel anti-STEAP1 TCE, Xaluritamig, in mCRPC.
In parallel, CAR-T therapies have shown feasibility and early signals of anti-tumour activity. However, their clinical impact remains constrained by obstacles such as T-cell exhaustion, the immunosuppressive TIME, and the logistical complexities of manufacturing. To address these limitations, the field is now experimenting with tandem and bispecific CARs, memory-enriched cells, and switchable or universal CARs.
Future Directions:
One of the central lessons we drew from the last decade of clinical trials is that PD-1 inhibition alone is insufficient for the vast majority of prostate cancers. The challenge lies in overcoming the profoundly “cold” TIME that thwarts immune activation. Future success will depend on novel strategies that can bypass or reprogram this suppressive biology. TCEs, in particular, are emerging as a promising approach to directly mobilise T cells against tumour cells, with the potential to overcome challenges that have led to failures in checkpoint inhibitor therapy. CAR-T platforms may also play a role if adapted to the unique hurdles of prostate cancer biology.
For clinicians, the practical takeaway is to consider PD-1 inhibition only in biomarker-selected subsets today, while remaining vigilant for trial opportunities testing next-generation approaches. For researchers, the priority is to refine these novel modalities and explore combinations that can unlock immune responsiveness in prostate cancer’s cold TIME.
Conclusions:
We do not believe that prostate cancer should be dismissed as universally resistant to immunotherapy. Instead, we argue that overcoming its “cold” biology will require careful patient selection, rational trial design, and novel drug development. Success in these domains could finally position immunotherapy as a core treatment pillar – joining androgen receptor–targeted therapy, chemotherapy, PARP inhibition, and radioligand therapy – in the evolving management of metastatic prostate cancer.
Written by: Liam Dwyer,1,2 Claudia Leslie,1 Rhiannon Mellor,1,3,4 Tahlia Scheinberg,1,2,4 Renea A Taylor,5-8 Lisa G Horvath,2-4,9
- Chris O'Brien Lifehouse, Camperdown, NSW, Australia.
- School of Medicine, University of Sydney, Camperdown, NSW, Australia.
- School of Medicine, University of NSW, Kensington, NSW, Australia.
- Garvan Institute of Medical Research, Darlinghurst, NSW, Australia.
- Monash Biomedicine Discovery Institute, Cancer Program, Department of Physiology, Monash University, Clayton, VIC, Australia.
- Cancer Immunology Program, Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
- Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, Australia.
- Cabrini Institute, Cabrini Health, Malvern, VIC, Australia.
- Chris O'Brien Lifehouse, 119-143 Missenden Road, Camperdown, NSW 2050, Australia.