### Physical diffusion - Positive pressure and drug penetration, immune infiltration. >Solid  tumor penetration isn't really related to this though, it has a lot more to do with the fact that it is physically difficult for a molecule to diffuse through the many layers of cells that make up a solid tumor.  When you take a drug, it generally ends up in your bloodstream and from there must diffuse through the lipid bilayers that encapsulate cells (whether they be cancer cells or not) in order to reach their target. This diffusion is a big barrier when it comes to designing drugs,  because most things won't passively diffuse through lipid bilayers. >A successful small-molecule drug will be able to 1) bind to its target effectively enough to stop that target from doing some disease-causing thing, 2) not bind to other things that are important for cellular function, and 3) get into the cell in the first place, without being  broken down before it gets there. >Balancing all 3 of these requirements  is tricky, but rules of thumb have been developed for 3) that help guide the design of small molecules. >Perhaps the most important  guideline for 3) is size. Most small molecule drugs (anything that you  take in a pill, along with many chemotherapeutics) are designed to be < 500 Dalton. Once you get over 800-1000 Da diffusive cell  penetration is rare (there are interesting outliers, cyclosporine  cruises through lipid bilayers despite weighing in at ~1200 Da).  Immunotherapy generally involves retraining your immune system by introducing antibodies (~150 kDa+) or whole T-cells. These modalities can generally only target things on the outside of cells, because there  is no way they're getting inside, and they certainly won't be able to  pass through the many layers of cells that make up a solid tumor. >tl;dr  is that immunotherapeutic agents won't be able to penetrate solid  tumors by diffusion because they (the antibodies and cells involved in  immunotherapy) are too big, and there isn't any other mode of entry. I  do wonder if a true immune response would need to penetrate at all  though, because presumably T-cells would break down a solid tumor layer  by layer if the appropriate antigen was present. I'm not sure how  correct this line of thinking is though.               [https://news.ycombinator.com/item?id=30192209](https://news.ycombinator.com/item?id=30192209)