New Therapeutic Horizons in Prostate Cancer: Targeting Tumor Immunity and Overcoming Drug Resistance

Preclinical data in prostate cancer models suggest that the tumor's ability to manipulate its immune environment not only aids survival but also reveals therapeutic targets, including pathways such as VEGF/neuropilin-2. In certain contexts, this axis may help sustain PD-L1 expression; when disrupted, it can diminish tumor defenses and open exploratory avenues for treatment, as illustrated by a preclinical study examining NRP2–PD-L1 regulation.

While VEGF/neuropilin-2 is a potential contributor, PD-L1 expression reflects a broader set of immunologic interactions that remain under active investigation.

Signals from early-phase studies suggest that concurrent targeting of VEGF pathways and PD-1/PD-L1 may warrant further evaluation, but definitive clinical benefit in prostate cancer remains to be established. Patients facing resistant disease often oscillate between hope and challenge as immunity-driven strategies continue to evolve.

Managing resistance is a linchpin of therapy, particularly as adaptations in androgen receptor (AR) pathways diminish the efficacy of traditional approaches. Here, cross-resistance emerges, where alterations in AR signaling and treatment-emergent neuroendocrine prostate cancer (t-NEPC) lessen the impact of standard AR inhibitors, as observed in recent analyses of AR-targeted therapy resistance.

These phenotypic shifts can appear after exposure to potent AR pathway inhibitors, with molecular reprogramming that reduces dependence on androgen signaling. Clinically, this may manifest as aggressive visceral disease, lower PSA expression, and resistance to subsequent AR-directed lines—features that complicate both prognosis and sequencing decisions.

Looking ahead, the field is working to translate mechanistic insights from preclinical models—such as VEGF/NRP2’s potential influence on PD-L1—into clinical hypotheses that can be tested rigorously. Parallel efforts to detect and manage t-NEPC early, including with imaging and pathology review when disease biology shifts, may help anticipate resistance trajectories.

Above all, progress will depend on integrating biologic understanding with pragmatic trial design and routine-care realities. As datasets mature, clinicians will be better equipped to identify who benefits from immune-modulating strategies and how to mitigate resistance when it emerges.