Accumulating evidence from randomized phase 3 trials in multiple tumor types supports the application of neoadjuvant or perioperative immunotherapy to significantly enhance clinical benefit in patients with resectable solid tumors. While systemic immunotherapy in this setting can be very effective, immune-related toxicity and resistance remain important challenges. Local administration of immune checkpoint blockade and/or other immune modulatory agents at lower doses offers a promising alternative strategy. Access to the proximal tumor microenvironment and tumor-draining lymph nodes (TDLNs) minimizes systemic exposure and potentially mitigates toxicity without compromising efficacy. Local neoadjuvant immunotherapy may enable more potent immune priming and activation within preserved TDLN, potentially reducing both local and distant recurrence rates and improving clinical outcomes. The availability of post-treatment resection specimens allows for the subsequent in-depth analysis of induced immune responses and co-evolving resistance mechanisms. Notwithstanding these potential advantages, challenges remain, such as lack of consensus on preferred delivery techniques, optimal (combinatorial) agents, dosing, and timing of administration. Carefully designed clinical trials, randomized against systemic administration, are needed to address these issues, establish durable clinical benefit, and guide broader implementation of locally administered neoadjuvant immunotherapy.
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