Antibody-drug conjugates (ADCs) can cause immunogenic cell death, remodeling the tumor microenvironment and enhancing antigen presentation. This mechanism could potentially make PD-L1 negative ('cold') tumors responsive to immune checkpoint inhibitors, creating a strong rationale for investigating ADC-immunotherapy combinations in this patient population.

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 rationale for combining ADCs with checkpoint inhibitors extends beyond additive effects. Preclinical data shows ADCs can increase T-cell infiltration into the tumor, potentially turning immunologically 'cold' tumors 'hot.' This offers a promising synergistic strategy, especially for PD-L1 negative patients who typically don't respond to immunotherapy alone.

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.

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.

Antibody-drug conjugates can disrupt the tumor microenvironment, leading to an influx of immune cells. This may turn an immunologically "cold" tumor "hot," creating a rationale for re-challenging with an immune checkpoint inhibitor, even if the patient's tumor previously did not respond to one.

While immunotherapy was a massive leap forward, Dr. Saav Solanki states the next innovation frontier is combining it with newer modalities. Antibody-drug conjugates (ADCs) and T-cell engagers are being used to recruit the immune system into the tumor microenvironment, helping patients who don't respond to current immunotherapies.

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.

Clinical trial data suggests immunotherapy's timing is crucial in early-stage TNBC. Given with chemotherapy before surgery (neoadjuvant), it improves outcomes. However, when given alone after surgery (adjuvant), the IMPASSION 030 trial showed no benefit and was halted for futility, indicating pre-surgical tumor priming is essential.