Trials like the dostarlimab study in rectal cancer and NICHE in colon cancer show neoadjuvant immunotherapy can induce profound responses in MSI-high tumors. This is creating a new paradigm where major surgery might be avoided entirely for some patients, marking a significant shift in treatment strategy.

The success of neoadjuvant immunotherapy trials like Niagara and those with EV-Pembro means most patients will receive immune therapy before surgery. This fundamentally shifts the clinical landscape, making the question of starting adjuvant immunotherapy less relevant as perioperative treatment becomes the standard.

The key rationale for neoadjuvant immunotherapy is that an in-situ tumor provides a rich source of antigens. Treatment primes the immune system against these targets, creating a powerful, systemic immunological memory that can effectively eliminate micrometastatic disease before and after surgery.

While neoadjuvant-only immunotherapy has a strong rationale, a patient-level cross-trial comparison of CheckMate 816 (neoadjuvant) and 770T (perioperative) suggests the addition of adjuvant therapy improves event-free survival, favoring a full perioperative approach.

Unlike in rectal cancer where pre-surgical shrinkage is key, the primary objective of neoadjuvant immunotherapy in operable colon cancer is to activate a systemic immune response. This targets and eliminates unseen micro-metastases, the true cause of recurrence, thereby increasing the overall cure rate.

Standard cancer surgery often removes lymph nodes—the factories producing immune cells. Administering immunotherapy *before* this destructive process is critical. It arms the immune system while it is still intact and capable of mounting a powerful, targeted response against the tumor.

Administering immunotherapy while the primary tumor and lymph nodes are intact allows them to act as an "in-situ vaccine." This generates a more diverse and powerful systemic immune response against cancer cells throughout the body compared to treating after surgical removal of these antigenic sources.

Historically, resectability was a static, pre-treatment judgment. With neoadjuvant immunotherapy causing significant tumor and nodal downstaging, surgeons must now dynamically re-evaluate resectability after systemic therapy, expanding surgical options for patients previously deemed inoperable.

Unlike chemotherapy, neoadjuvant immunotherapy appears more effective than adjuvant therapy because it leverages the in-situ tumor and its associated lymph nodes as a 'training ground.' This allows the immune system to generate a robust, specific anti-tumor response before the primary tumor and nodal basin are surgically removed.